2-lower alkyl steroidal compounds



United States 2,852,538 Z-LOWER ALKYL STEROIDAL COMPOUNDS Mary A. Scheri, Kalamazoo, and Gunther S. Foulxen and John A. Hogg, Kalamazoo Township, Kalamazoo County, MiclL, assignors to The Upjohn Company, 5 Kalamazoo, Mich., a corporation of Michigan No Drawing. Application November 16, E55

Patented Sept. 16, 1958 lie QIE

Serial No. 547,313 14 Claims. (Cl. 260-39145) (H CH9 OHHOR CHzOR +13 2711 A HO CHa O OM CH3 R1OC3== I II 0: O:

CH! CHa CHgOH ii'lHgQR JIH CH 1 1 III CH3 CH3 GHaOR CHzOR on C 3 CH:

CHQOR CHzOR HOR CHOR ----OH J:--- OH R1- V-IIl- VII CH3 CH3 OHzOR CHzOR CHOR b11012 I-WOH l---oH O HO 0H3\ CH3 Ri- R1 1 IX X o 0:

([IHQOR OHOR CH3 Riwherein R is selected from the group consisting of hydrogen and acyl in which the acyl radical is of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, R is a lower-alkyl containing from one to eight carbon atoms, M is an alkali metal of atomic weight 6 thru 41 r .and X is a halogen of atomic weight 33 thru 136.

[trans1-pregnadien-3-one or the corresponding 21-ester thereof (III), which is hydrolyzed with an alkali base, such as an alkali alkoxide to give 2-lower-alkyl-11,l3,21- dihydroxy-4, 17 (20) [trans] -pregnadien-3-one (IV). Esterification of (IV) is productive of the 21-ester, 2-lowerdien-3-one (V). The ester (V) is thereupon treated with osmium tetroxide to give the corresponding intermediate 17,20-osmate which is decomposed with sulfur dioxide gas in water (sulfurous acid) to give 2-lower-alkyl- 11/3,17a,20fi,21-tetrahydroxy-4-pregnen-3-one 21 acylate (VI). Compound (VI) by hydrolysis in a mildly alkali medium (preferably in a nitrogen atmosphere) provides the free tetrol, 2-lower-alkyl-115,17a,20fi,2I-tetrahydroxy- 4-pregnen-3-one which can be esterified in conventional manner to provide the diester, 2-lower-alkyl-11fi,17adihydroXy-20fl,21-diacyloXy-4-pregnen-3one. Oxidation of this diester with chromic acid produces 2-lower-alkyl- 17u-hydroxy-20B,21-diacyloxy-4 pregnene 3,11 dione. Dehydration of 2 lower alkyl-l1fl,17u,20fi,21-tetrahydroxy-4-pregnene-3-one 205,21-diacylate illustratively with a hypohalous acid and then with anhydrous sulfur dioxide produces 2-lower-alkyl-17ot-hydroxy-20,21-diacyloxy-4,9(11)-pregnadien-3-one (VII). Addition of a hypohalous acid such as hypochlorous or hypobromous acid results in 2-lower-alkyl-9ct-halo-1lfi,l7 x-dihydroxy- 205,21-diacyloxy-4-pregnen-3-one (VIII) which by treatment with a base such as anhydrous potassium acetate yields the epoxy compound 2-lower-alkyl-9B,llfi-epoxyl7u-hydroxy-20fi,21-diacyl0xy-4 pregnen 3 one (IX). Treatment of epoxy compound (IX) with hydrogen fluoride or other hydrogen fluoride releasing agents provides the active fiuoro derivative, 2-lower-alkyl-9a-fiuoro- 11e,17a-dihydroxy-20fi,21-diacyloXy-4 pregnen 3 one (X). Oxidation of compound (X) with chromic acid in acetic acid provides the 2-lower-alkyl-9a-fiuoro-17ahydroxy-20,8,21-dihydroxy-4-pregnene-3,11 dione (XI). Oxidation of compound VIII in the same manner as compound X results in other 2lower-alkyl-9a-halo-17ahydroxy-ZOQZ1-diacyloxy-4-pregnene-3,1l-diones wherein halo is chloro, bromo or iodo. Hydrolysis of the esters provides the free alcohols of these compounds which are useful either per se or as intermediates to produce by reesterification more desirable esters of the free alcohols, such as 21-monoesters of 2-lower-alkyl-115,17a,20,8,21- tetrahydroxy-4-pregnen-3-ones, 2-lower-alkyl-17a,20,6,2ltrihydroxy-4-pregnene-3,1l-diones and their Qa-halo derivatives.

It is an object of the present invention to produce certain 2 substituted 3 keto 11 oxygenated 4- pregnenes. It is a particular object of the present invention to produce 2 substituted 3 keto 11 oxygenated-4-pregness selected from the group consisting of alkali metal enolates of 2-lower-alkyloxyoxalyl-115,21- dihytlroxy 4,17(20) pregnadien 3 ones, and 2 lower alkyloxyoxalyl 11/3 hydroxy 21 acyloxy- 4-,l7(20) pregnadien 3 ones, 2 lower alkyloxyalyl- 2 lower alkyl 1113,21 dlhydroxy 4,1?(20) pregnadien 3 one, and 2 lower alkyloxy oxalyl 2 lower allzyl 11B hydrox z 21 acyloxy 4,17(20)- pregnadien 3 one, 2 lower alkyl 115,21 dihydroXy 4,l7(20) pregnadien 3 one, 2 lower alkyl 11/3 hydroxy 21 acyloxy 4,17(20) pregnaclien 3- one, 2 lower alkyl ]l,B,l7zx,2QB trihydroxy 21- acyloxy 4 pregnen 3 one, 2 lower alkyl 11,63,170;- dihydroxy 20,21 diacyloxy 4 pregnen 3 one, 2- lower alkyl ll/i,l7oc,20,21 tetrahydroxy 4 pregnen 3 one, 2 lower alkyl 17oz hydroxy 20,21- diacyloxy 4 pregnene l 3,11 dione, 2 lower alkyl- 17a,20/8,2l trihydroxy 4 pregnene 3,11 dione, 2- lower alkyl 17a hydroxy 203,21 diacyloxy 4,9- (ll) pregnadien 3 one, 2 lower alkyl l7o:,20fi,2l-

I acid such as trimethylacetyl chloride.

trihydroxy 4,9(11) pregnadien- 3, one, 2 loweralkyl 90c halo 11 3,1704 dihydroxy 2013,21 diacyloxy 4 pregnen .3 one; 2 lower alkyl 9a halo- 1li3,17u,20,8 trihydroxy 21 trimethylacetoxy 4- pregnen 3 one, 2 lower alkyl 9 halo 11,8,17a,20,21- tetrahydroxy 4 pregnen 3 one, 2 lower alkyl- 9(l1) oxido 17oz hydroxy 205,21 diacyloxy 4- pregnen 3 one, 2 lower alkyl 9oz halo 171xhydroxy 20,8,21 diacyloxy 4 pregnene 3,11 dione, 2 lower alkyl 9a halo l7a,20}9 dihydroxy 21- trimethylacetoxy 4 pregnene 3,11 dione, and 2- lower alkyl 9oz halo 17m,20,21 trihydroxy 4- pregnene-3,ll-dione wherein the lower-alkyl contains from one to eight carbon atoms, inclusive; the alkali metal is of atomic weight six thru forty, inclusive, the acyl radical is of an organic carboxylic acid, preferably of a hydrocarbon carboxylic acid, containing from'one to eight carbon atoms, inclusive, and halo denotes the halogen atoms of atomic weight 17 thru 130, inclusive'. 'It is another object of the instant invention to provide a proc ess for the production of the 2-substituted-3-keto-11- oxygenated-4-pregnenes, especially for the production of 2-alkylated Reichsteins substance E (compound VI) and 2-alkylated Reichsteins substance 'U, the 2013,21-diesters thereof, and the 9a-halo derivatives (VIII, X, XI) thereof. Other objects will be apparent to those skilled in the art to which this invention pertains.

The compounds of the instant invention are important intermediates in the production of highly active adrenal cortical hormones and in addition possess activity per so. For example, oxidation of 2-lower-alkyl-1 1B,l7a,20;8-trihydroxy-2l-acyloxy-4-pregnene-3-one with manganese dioxide produces the highly active Z-methylhydrocortisone, whilesimilarly oxidation of 2-lower-alkyl-9ot-halo-l1B,-

17a,2013-trihydroxy-21-acyloxy-4-pregnen-3-one and hydrolysis produces the extremely active series of 2'-alkylated- 9a-halohydro-cortisones, of which the 2-m'ethyl-9a-fluorohydrocortisone is one of the most'important members. Similarly, om'dation of the corresponding ll-keto analogs, such as Z-IOWEI-alkYl-1706,20fi-CllhYdlOXY-2leElCYlOXY-F pregnene-3,l1-dione and the corresponding 90c-l'13l0 compounds thereof, such as the 2-methyl-9a-fluoro-170,20fidihydroxy-21-acyloxy-4-pregnene-3,1l-dione with manganese dioxide provides the corresponding Z-methyl-cortisone respectively 2-rnethyl-9a-fluoro cortisone 21-esters. All of these compounds are important adrenal cortical steroids'having pronounced cortisone like activity. While the chloro, bromo, and iodo derivatives of these 2-alky-lated cortisone and hydrocortisone compounds have activity of considerable significance, the greatest activity has been found in those having in the 9a-position a fluorine atom.

The selective 2l-esters possessing a ZOB-free' alcohol group are necessary in these oxidations, are either obtained during the process as seen in the example, or are obtained by selective esterification carried out by reacting the selected 2 alkyl 11 oxygenated 17c,20f3,2l trihydroxy-4-pregnen-3-one with an acyl halide of a hindered The Z-methyl- 1l' 3,17oc,20,21 tetrahydroxy 4 pregnen 3 one per se and the esters thereof as well as the 2-methyl-9u-fiuoro- 115,l7a,20,21-tetrahydroxy-4-pregnen-3-one and the esters thereof have anti-adrenocortical hormonal activity inhibiting, for example, the decrease of adrenal weight by cortisone or hydrocortisone and are therefore usefully administered in prolonged cortisone or hydrocortisone treatment in order to prevent atrophy of the adrenal glands. Similarly the corresponding ll-keto analogs 2- methyl 17u,20;3,21 trihydroxy 4 pregn'ene 3,11- dione and the halocompounds such as 2-methyl-9a-flu'oro- 17oz,20fi,2'1 trihydroxy 4 pregnene 3,11 dime and esters thereof are useful as anticortical hormonal agents in the same manner as the corresponding" IIfl-hyd'roxy analogs. These compounds also show' mineral corticoid activity of a low degree which makes them -particularly yalua-ble in" combinations with cortisone, hydrocort-isone,

6 or the'n cortisone and n -hydrocortison'e to prevent atrophy of the adrenal glands, as produced by cortisone, hydrocortisone and the A analogs thereof, while not increasing unduly the mineral corticoid activity (salt retention) of the before-mentioned hormones.

The starting materials for the instant process are 1113,21 dihydroxy 2 methyl 4,17(20) [trans]- pregnadien-3-one 21-acylates such as the Zl-acetate, other esters thereof or the free alcohol. 11,8,21-dihydroxy- 4,17 (20)-[trans]-pregnadien-3-one and the 21-acetate thereof have been described by Hogg et al., J. Am. Chem. Soc. 77, 4436 (1955). Other 2 l-esters of 11,8,2l-dihy droxy 4,17(20) [trans] pregnadien 3 one are prepared by esterification such as shown in Preparations l and 2.

in carrying out the process of the present invention,

1 15,2 l-dihydroxy-4,17 (20) [trans] -pregnadien-3-one or a selected Til-ester thereof is admixed with a selected alkali metal condensation catalyst and a dialkyl ester of oxalic The order of mixing to alkanol, or tertiary butyl alcohol are usually the preferred solvent. The preferred condensation agent is a lower-alkyl. oxalic acid ester such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, phenyl, benzyl, or the like oxalic acid esters, with methyl and ethyl oxalate preferred. The condensation is generally conducted at a temperature between about zero degrees centigrade and the boiling point of the reaction mixture. The reaction proceeds With satisfactory rapidity at between about room temperature (twenty to thirty degrees centigrade) and about seventy degrees centigrade, and temperatures substantially above or below this range are therefore not required. The time necessary to obtain substantially com-- plete reaction varies considerably, between about five minutes and several days, depending upon the reaction solvent, the reaction temperature, the selected ester of oxalic acid and the alkali-metal condensation catalyst employed. When methyl or ethyl oxalate and tertiary butyl alcohol are employed at about fifty degrees centigrade, the reaction is usually more than half completed in a few minutes. The condensation step is usually carried out in the absence of any significant amounts of water in any form of the reaction as would be expected in the reaction of this type. To insure the essentially complete exclusion of water from the reaction mixture, the solvent is carefully dried with a drying agent, such as, for example, anhydrous sodium sulfate, calcium :sul-

fate, calciunr chloride, phosphorus pentoxide, sodium, or the like, or when an aromatic hydrocarbon is used as a solvent, a portion of the solvent is distilled before using.

Alkali metal condensation catalysts include the alkali metal alkoxides, wherein the alkyl radical of the alkoxy group contains from one to eight carbon atoms, inclusive, and wherein the alkali metal is of atomic weight six thruforty, such as sodium.methoxide, sodium ethoxide, sodium isopropoxide, potassium tertiary butoxide, lithium methoxide, and the like, the alkali metals, the alkali metal hydrides, alkali metal amides e. g.-, sodium amide, and alkyl alkali metals, for example, tiphenylmethyl sodium, and the like. Of these, the alkali metal alkoxides, especially sodium methoxid'e and sodium ethoxide are a preferred for'their convenience and consistently satisfac- 1 solvent,. or insitu in the aik'a'nol in which said alkali metal alkoxide was prepared. When potassium is used, it is usually used as the solution formed by its reaction with tertiary butyl alcohol according to procedures well known in the art. The theoretical alkali metal condensation catalyst required is one mole per mole of steriod. Somewhat more than the theoretical amount is usually employed.

The thus produced alkali metal enolate may be separated by the addition of a large volume of an organic solvent in which the alkali metal enolate is insoluble, such as ether, pentane, or benzene, for example. Another method of producing somewhat purer alkali metal enolate comprises acidification of a cold aqueous solution of the thus precipitated alkali metal enolate to precipitate the free enol and then treating a solution of the free enol in ether or benzene with a chemical equivalent of sodium methoxide, thus reprecipitating the sodium enolate. When the condensation is carried out in the presence of a substantial amount of methyl or ethyl alcohol the removal of said alkali by distillation at reduced pressure before the addition of an additional amount of solvent is preferred, if a high yield of isolated product is to be obtained.

The thus produced alkali metal enolate of 2-loweralkyl 11,8,21 dihydroxy 4,17(20) [trans] pregnadien-3-one or the corresponding 21-ester thereof is alkylated by the addition of a lower alkyl halide, such as methyl iodide, ethyl iodide, propyl bromide, isopropyl iodide, butyl chloride, bromide and iodide, pentyl chloride, bromide and iodide, hexyl, heptyl, and octyl chloride and bromides, phenyl bromide and iodide, benzyl chloride, bromide or iodide, and the like. In the preferred em bodiment the alkyl halide is added to'the steroid dissolved in an organic solvent such as methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, pentanes, hexanes, or the like. After adding the alkyl halide to the solution the reaction is continued for several hours, for example, about eight to about 72 hours at a reaction temperature of about room temperature, twenty to thirty de rees centigrade. Higher temperatures shorten this reaction time considerably. A convenient method of alkylation was the addition of the selected alkyl halide to the reaction product resulting from the condensation step, preferably after the decomposition of any excess alkali metal condensation catalyst. Satisfactory yields are also obtained by stirring the solution of the free active methylene compound, the metal enolate of 2-alkoxyoxalyl- 115,21 dihydroxy 4,17(20) [trans] pregnadien 3- one or esters thereof with the selected alkyl halide.

Alkali metal alkylation catalysts such as sodium or po- The reversal step of the present invention involves the removal of the alkoxyoxalyl group from the 2-position leaving the alkyl group at the 2-position thus producing a Z-lower-alkyl-i15,21-dihydroxy-4,17(20)-[trans]-pregnadien-3-one or the respective 21-ester thereof. The reversal step of the present invention is produced by the alkali metal alkylation catalyst, sodium or potassium carbonate, in the presence of water or a lower-alkanol. The reversal reaction is especially promoted by the presence of hydroxide or alkoxide, particularly methoxide and ethoxide ions. After reacting the 2-alkyl-oxyoxalyl 2 aikyl 11 6,21 dihydroxy 4,17(20) pregnadien-3- one or a 21-ester thereof with a base such as methanol and sodium methoxide, ethanolic methoxide at room temperature, the mixture is poured into a large amount of water and the product is separated by conventional means such as extraction, filtration, or the like, and the material, a 2-alkyl-l1fl,21-dihydroxy-4,17(20)-[trans]- pregnadien-3- one (or a 21-ester thereof), is purified by recrystallization, additional extraction of impurities, chromatography, or the like, as deemed necessary.

20,8,21-diacyloxy-4-pregnen-3-ones.

The 21-acyloxy group of a 2-lower-alkyloxyoxalyl-2- alkyl-1lfl-hydroxy-Zl-acyloxy 4,17(20) [trans] pregnadien-3-one is removed in the reversal reaction if the acyl group is of a simple unhindered acid such as acetic, propionic, or the like. If the acyl group is of a sterically hindered acid such as dineopentylacetic, trimethylacetic, or the like, the 2l-ester group remains intact. In many other cases, a mixture of the ester and the free alcohol is obtained. If desired, the ester is reformed by conventional procedure, such as reacting the obtained 2-lower-alkyl 11 6,21 dihydroxy-4,17(20)-[trans]-pregnadien-3-one with an acid anhydride or acid halide of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms in pyridine or in a neutral organic solvent such as benzene, toluene, or the like.

The thus obtained 2-lower-alkyl-11,8,21-dihydroxy- 4,17(20)-[trans] 4 pregnadien-3-one or the 21-acyloxy esters thereof is hydroxylated with osmium tetroxide and aqueous sulfur dioxide to give the corresponding 2-lower-' alkyl-1 1B, 17a,20[3,21-tetrahydroxy-4-pregnen-3-one. For this purpose the 2 lower alkyl 115,21 dihydroxy- 4,17(20)-[trans]-pregnadien-3-one is dissolved in an organic solvent such as tertiary butyl alcohol, pyridine, diethylether, dioxane, isopropyl alcohol, tetrahydrofuran, tertiary amyl alcohol, ethanol and methanol or the like, with tertiary butyl alcohol preferred, and reacted with the metallic oxide, preferably osmium tetroxide. Other oxides which are operative include manganese dioxide,

vanadium pentoxide, chromium trioxide, pertungstic acid, permolybdic acid, selenium dioxide, and the like. The proportion of osmium tetroxide or other metallic oxide is preferably equal to one mole of metal oxide to one mole of steroid since the hydroxylation reaction requires the intermediate osmate or other peracid ester, however, smaller or larger proportions of the metal oxide are operative. The reaction is carried out at a temperature between minus ten and plus seventy degrees centigrade,

preferably at room temperature between fifteen and thirty degrees Centigrade. The time of reaction is from several minutes such as five minutes to 24 hours. Long contact of the metal oxides with the steroid produces a high yield in reaction product. The thus obtained ester, illustratively a 17,20-osmate, is hydrolyzed by the addition of water to the ester. If a water miscible solvent such as tertiary butyl alcohol, dioxane, ethyl or methyl alcohol is chosen for the production of the osmate, the addition of water is usually made to the solution containing the osmate ester. If the ester was produced in a solvent immiscible with water, the osmate is separated by evaporating the solvent in vacuo and using without further purification the solid steroid osmate ester. position of the ester is promoted by adding an acid to the solution, preferably an acid with reductive quality The illustratively by recrystallization or chromatography, as

deemed necessary.

Hydrolysis of this material by alkali, preferably in a nitrogen atmosphere, produces the free tetrol, 2-loweralkyl-11,6,l7e,20fi,21-tetrahydroxy 4 pregnen 3 one. Esterification of the tetrol with halides and hydrides of organic carboxylic acids or hydrocarbon carboxylic acids' containing from one to eight carbon atoms gives'ordinarily the diesters, 2-lower-alkyl 11317:: dihydroxy- The decom-' If acid halides or.

I acid anhydrides of highly hindered acids'are used, such s xns h la e ch orid neor n y -a yl bromi e or the like are used, selective 'estct ili cation in the 21-position, is obtained. In this manner 2-lower-alkyl-11,8,17a,20 8- trihydroxy-Zl-acyloxy-4-pregnen-3=ones can :he produced which are valuable for the further oxidation to the corresponding hydrocortisone 21-,esters.

Oxidation of the diester, a Z-lower-alkyl-l15,17a-dihydroxy-2Ofl,21-diacyloxyrt-pregnen-31one with chromic acid is productive oftthc corresponding 2-lower-alkyl-17ahydroxy-20B,2 l-diacyloxya lkpregnenes3 1 l-dione. V

In order to obtain the corresponding 9-a-halo compounds, the 2-lower-alkyl-11,8,Weill 5,2l-tetrahydroxytpre nc-n-fi- 2 Br -d acy ate .is d hydrated to the co responding 2-lower-alky1-17u,20fi,2l-trihydroxy 4 pregnen-3.-one 20B,21-diacy l ate by methods known in the art, suitable dehydrating agents are for example phosphorus cxr h ride h dr h oric acid o sulfu c aci i acetic acid, in pyrolysis as shown ,by U, S. Patents 2,640,838 and 2,640,839. In the preferred embodiment of the present invention the dehydration is effected by reacting theil 1phydroxy compound with an N-haloaniide or N haloimide in an organic base and treatingthe thus produced intermediate ll-hypohalite with dry sulfur dioxide in an organic base. As reagents for the production of an ll-hypohalite, the N-haloamide or N h-a'loimide are used wherein the halogen has an atomic weight from 34 to 130, inclusive, preferably chlorine or bromine. Examples of such compounds are N-chloroacetarnide, N-bromoacetamide, N-chlorosuccinimide, N-bromosuccinimide, .N-iodosuccinimide, 3-bromo-5,S-dimethylhydantoin and 1,3-dibromo-S,S-dimethylhydantoin. Ordinarily an amount in excess of a molar equivalent, calculated on the starting llp-hydroxy steroid, is employed. The base employed in the production of the ll-hypohalite are tertiary amines wherein the amino nitrogen is a member of an aromatic ring, for example, the pyridines, that is, pyridine, alkylpyridines, piccoline, lutidine, collidine, conyr-ine, parvuline, or the like, or lower fatty amides such as formamide, methylformarnide and dimethylformamide. The base is preferably employed in a large molar excess, calculated on the starting ll 8=hydroxy steroid, for example, ten molar equivalents, and is preferably the sole reaction solvent. The reaction to produce an ll-hypohalite is generally conducted under anhydrous conditions preferably containing less than 0.1 molar equivalent of water calculated per mole of steroid. Large proportions of water decrease the yield. The temperature of the reaction is between minus forty and plus seventy degrees centigrade, the lower limit being determined by the solubility of the reaction and solvents and the upper limit being determined by the amount of side reaction which normally accompanies the reaction involving any halo compounds at higher temperatures. Ordinarily, room temperature (twenty to thiry degrees centigrade) is preferred for convenience and the consistently high yields of the desired product which are obtained at this temperature. A reaction period between five minutes to three hours is usual y emp yed a hi he temper tur s. abov thirty grees centigrade, short reaction times being sufiicient to produce completeness of the reaction,

" The thus produced 2-lower-alkyl-lle,l7a,20fl,2l-tetrahydroxy-4-pregnene3-one llfishypohalide 20,21-diacy1ate is then treated with anhydrous sulfur. dioxide in the presence of an organic base as described hereinbefore. The anhydrous sulfur dioxide can be in the form of gaseous or liquid sulfur dioxide or in the form of a material which in situ produces sulfur dioxide, for example, alkali metal hyposulfite. The reaction temperature ranges substantially within minus forty and plus seventy degrees centigrade and preferably room temperature (twenty to thirty d r s n gr d The thu ob ained pr duct a. 2.- l a kvkl @2 52univer i y- ,2(1 1) P gnadien a B-one 2 t l,2;l-diacylate is isolated by conventional means each as extractionfrom the reaction mixture afterthe reaction mixture has been :Poured ,int'o' excess of water. .Qrganic water-immiscible solvents such as ether, chloroform, methylene chloride, carbon tetrachloride, :ethyl acetate, benzene, hexanes, .or the like, are used for the extraction. The thus obtained extracts are conveniently washed, dried and thereupon evaporated to give, the crude 2-lower-alkyl-l7rx,2.0b,2l-tr ihydroxy-4,9(l1) pregnadien-3-one 20,8,21-diesters which are purified by conventional means such as recrystallization or chromatography, as deemed necessary. The thus obtained 2- lower-alkyl-l7u,20/3,2l-trihydroxy 4,9(11) pregnadien- 3-one 206,2l-diacylate 'is'converted to 2-lower-alkyl-9ahalo-11 8,l7a,20fi,2l-tetrahydroxy-4-pregnen 3 one di acylate by adding a hypohalous acid such as hypochlorous or hypobromous acid. The hypohalous acid is usually added by reacting an .N-halo acid amide .01 an .N-halo acid imide with an acid to produce the hypohalous acid in situ. In the preferred embodiment of the invention, the steroid, a 2.- a1 kyl-'17a,20/3,2lrtrihydroxy-4',9(11:)- pregnadien-3-one or the esters thereof is dissolved in .an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol, or the like, and reacted at room temperature with the hypobromous .01? hypochlorous acid releasing agent in the presence of an acid. Such hypohalous acid releasing agent include the N bro-moacetamide, the N-chloroacetamide, the N-bromosuccinimide, the N-iodosuccinimide, or the like, in the presence of water and an acid such as per chloric acid, dilute sulfuric acid, or the like. The reaction is usually carried out at room temperature, between fifteen. to thirty degrees centigrade, however, lower or higher temperatures are operative for the process. The hypohalous acid releasing agent is generally used in one molar or slightly increased, for example, 25 percent increased amounts compared to mole of steroid. A large excess of the hypohalous acid releasing agent while operative is undesirable since the excess of hypohalous acid has a tendency to react on other positions of the molecule. The reaction period is rather short and may vary between about four to five minutes to one hour. At the end of the reaction time excess of hypohalous acid is destroyed by the addition of sodium sulfite or other sulfites or hydrosulfites. The thus produced product, a 2-lower-alkyl- 9a-halo-l1o,17a,20p,2l-tetrahydroxy-4-pregnene- 3 one 20,21-diacylate, wherein halo is of atomic weight between 33 and 130, is isolated from the reaction mixture by adding'excess of water and extracting the compound with organic solvents or by recovering the precipitated compound through filtration. A crude product thus obtained may be recrystallized from acetone and Skellysolve B hexane hydrocarbons to give pure 2-lower-alkyl-9a-halo- 1 1,8, l7tx,20fl,2 l -tetrahydroxy-4-pregnen-3 ones 2013,21-diacylate.

As shown before the diester thus obtained can be hydrolyzed to give the free tetrol, 2-lower-alkyl-9a-halo- 11B,l7a,20,6,21-tetrahydroxy-4 pregnen-3-one, which can be reesterified to give mono or diesters depending on the type and quantity of acylating agent used. Thus, using anhydrides or halides of hydrocarbon carboxylic acids of straight chain structure in excess produces diesters, 2- lower-alkyl-9a halo 11/3,17a,20,8,21 tetrahydroxy 4 pregnenPS-one 2013,2l-diacylates. If halides of sterically hindered acids are used, such as trimethylacetate, triethylacetate, dineopentylacetate, or the like, the corresponding 21-monoesters of 2-iower-alky1-9a-halo-11} ,17a,20/3,21- tetrahydroxy-4apregnenes are obtained.

oxidizing the 20fi,21-diester of a 2 -lo wer-alkyl-1lp,17ot, 206,21-tetrahydroxy-4-pregnen-3-one, with. chromic acid produces the corresponding pharmaceutically active 2- lower-alkyl-9a-halo-l7a,20[3,21-trihydr.oxy-4-pregnene 3i,

ll-dione 20fi,21-diacylate which by hydrolysis gives the free tetrol, 2-lower-alkyl-9u-halo-17u,20[3,2l-trihydroxyit 2-loWer-alkyl-9 3,11,8-epoxy 17a,205,21 trihydroxy 4 pregnen-3-one diesters, are prepared. In carrying out this reaction a 2-lower-alkyl-9a-halo-11fi,l7ot,20p,21-tetrahydroxy-4-pregnen-3-one diester is heated in solution with a mild base, and preferably in the absence of water to avoid hydrolysis of the ester groups.

The bases useful for the cyclization include anhydrous potassium acetate, sodium bicarbonate, sodium acetate, or the like, with potassium acetate preferred. Solvents such as methanol, ethanol, acetone, tertiary butyl alcohol, or the like, may be used. The reaction time is between one half hour and 24 hours; generally a period between three and twelve hours is sufficient. The thus obtained 2-lower-alkyl-9,t?,llfi-epoxy 17x,20B,21 trihydroxy 4 pregnen-B-one is isolated from the reaction mixture by pouring the reaction mixture into excess water and extracting with methylene chloride or other water-immiscible solvents such as ether, Skellysolve B hexanes, pentanes, benzene, ethyl acetate, chloroform, carbon tetrachloride, or the like. Evaporation of the solvent of the extracts produces the 2-lower-alkyl-9fl,115-epoxy-l7et, 20 8,21-trihydroxy-4-pregnen-3-one 20,8,21-diacylate.

The thus obtained 2-lower-alkyl-9,B,11-epoxy-17u,20fi, 2l-trihydroxy-4-pregnen-3-one 205,21-diacylate is thereupon reacted with 48 percent hydrofluoric acid in solution in the presence of a strong acid. As solvents for this reaction methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride or the like is useful, with methylene chloride preferred. As acid catalysts, perchloric acid, toluene-sulfonic acid, sulfuric acid or the like may be used. The reaction is carried out at room temperature (twenty to thirty degrees centigrade) preferably with stirring. The period of reaction is from one to 24 hours with a period from one to twelve hours usually sufficient. After the reaction is terminated, the mixture is poured into water and neutralized with a dilute base such as sodium bicarbonate, potassium bicarbonate, or the like. Excess of strong bases can also be used. The reaction mixture is then extracted with a water-immiscible solvent such as methylene chloride, the organic layer is separated from the water mixture, washed with water, dried and evaporated to give the crude 2- lower-alkyl-9a-flnoro 11,8,17a,20fi,21 tetrahydroxy 4 pregnen-3-one 205,21-diacylate. The thus obtained crude compound may be purified through recrystallization or chromatography as deemed necessary.

droxy-4-pregnen-3-one esters obtained by this process can be hydrolyzed to give the Z-IOWCI-alkYl-9oc-fill01'0- 11 3,17a,20[3,21-tetrahydroxy-4-pregnen-3-one which can be selectively esterified with acyl halides of hindered L bicarbonate in ethanol in a nitrogen atmosphere to give the free triol, 2-lower-alkyl-9u-fluoro-17a,205,21-trihydroxy-4-pregnene-3 ,1 l-dione.

The following examples are illustrated for the process and products of the present invention, but arenot to be construed as limiting.

PREPARATION 1 1 1 6,21 -dihydr0xy-4,1 7 (20) -[trans]-pregnadien-3-one 21- propionate One gram of 11,8,21-dihydroxy-4,l7(20)-[trans]-pregnadien-S-one was dissolved in ten milliliters of pyridine and ten milliliters of propionic anhydride. The mixture was allowed to stand at room temperature (about 22 to 25 degrees centigrade) overnight (sixteen hours) and thereupon poured into 100 milliliters of ice water. The thus precipitated 115,21 dihydroxy 4,17(20) [trans]- pregnadien-3-one 21-propionate was collected on filter paper and recrystallized from acetone Skellysolve B hexanes to give pure 11,6,21-dihydroxy-4,17(20)-pregnadien- 3-onc 21-propionate.

PREPARATION 2 115,21 dihydroxy-4,1 7( 20 -[trans]-pregnadien-3-one 21 benzoate 0.5 grams of 1113,21-dihydroxy-4,17(20)-[trans]-pregnadien-3-one was dissolved in five milliliters of pyridine and thereto was added three milliliters of benzoyl chloride. The mixture was maintained for a period of eighteen hours and thereupon poured into ice water. The water solution was extracted with three 25-milliliter portions of methylene chloride which thereafter were evaporated in vacuo and the solid material recrystallized from methyl alcohol to give pure 11 3,21-dihydroxy- 4, 1 7 20) -[trans]-pregnadien-3 -one 21 -benzoate.

In the same manner as shown in Preparations 1 and 2, other 21-organic carboxylic acid esters preferably hydrocarbon carboxylic acid esters containing from one to eight carbon atoms of 115,21-dihydroxy-4,17(20)-[trans]- pregnadien-3-one are produce by reacting the steroid compound with an acid halide or acid anhydride in a basic or neutral solvent such as pyridine, toluene, ben zene, ether, or the like, to give the corresponding 11 3,21- dihydroxy-4,17( 20)-[trans1-pregnadien 3-one 21-acylate comprising the butyrate, isobutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, B-cyclopentylpropio nate, toluate, gallate, salicylate, anisate, nicotinate, piperonate, benzenepropionate, chloroacetate, dichloroacetate, trichloroacetate, bromoacetate, iodoacetate, fluoroacetate, trifluoroacetate, benzenesulfonate, to1uenesul fonate, chlorobenzenesulfonate, para-nitrobenzenesulfonate, nicotinate, piperonate, 2-furoate, trimethylacetate, dineopentyl acetate, acrylate, crotonate, cinnamate, lac tate, acid titrate, acid succinate, dihydrogencitrate, or the like.

EXAMPLE 1 Sodium enolate of Z-ethoxyoxalyl-I 1 [3,21 dihydroxy- 4,1 7 (20) -[trans]-pregn adien-3-0ne 21-acetare A solution of 21 grams of l1,8,2l-dihydroxy-4,17(20)- [trans]-pregnadien-3-one 2l-acetate was dissolved in 400 milliliters of tertiary butyl alcohol and heated to seventy degrees centigrade. To this solution was added 16.6 grams of ethyl oxalate and the solution was stirred in an atmosphere of nitrogen for a period of five minutes; Thereafter 9.2 grams of sodium methoxide (37 grams of a 25 percent solution in methanol) was added. The mixture was cooled to 55 degrees centigrade and stirred for a period of thirty minutes. Thereafter 300 milliliters of ether was added and stirring was continued at 25 degrees centigrade for an additional period of thirty minutes. The thus precipitated sodium enolate of 2- ethoxyoxalyl-l15,21-dihydroxy 4,l7(20)-[trans]-pregnadien-3-one 21-acetate (Z-ethoxyoxalyl 11,8 1ydroxy-2lacetoxy-4,17(20) [trans] pregnadien-B-one) was recovered by filtration, the precipitate was washed with 200 milliliters of ether and then dried in vacuo at sixty degrees centigrade for a period of one and one half hours. Infrared spectrum in chloroform were in agreement with the postulated structure for 2-ethoxyoxalyl- 13 l15,21-dihydroxy-4,17 (20) -[trans]pregnadien 3-one 21- acetate.

EXAMPLE 2 (a) Refluxing 115,21 dihydroxy 4,17 (20) [trans]- pregnadien-3-one 21-propionate, dissolved in tertiary butyl alcohol, with methyloxalate in the presence of sodium methoxide produced the sodium enolate of Z-methoxyoxalyl 115,21 dihydroxy-v 4,17 (20)-[trans1-pregnadien-3-one 21-propionate.

(b) Treating 11 5,2 l-dihydroxy-4, 17 20 [trans]-pregnadien-3-one Zl-benzoate, dissolved in tertiary butyl alcohol, with ethyl oxalate in potassium ethoxide produced the potassium enolate of Z-ethoxyoxalyl-l15,21-dihydroxy-4,17(20)-[trans]-pregnadien-3-one 21-benzoate.

(c) Treating 115,21-dihydroxy-4,17(20)-[trans]-pregnadien-3-one 21-phenylacetate dissolved in tertiary butyl alcohol with butyl oxalate in the presence of lithium butoxide yielded the lithium enolate of 2-butox-yoxalyl- 115,21-dihydroxy-4,17(20)-[trans]-pregnadien 3-oue 21- phenylacetate.

'(a) Reacting l15,2l-dihydroxy 4,l7(20)-[trans]-pregnadien-3-one 2l-trimethylacetate with ethyl oxalate in the presence of potassium ethoxide yielded a potassium enolate of 2-ethoxyoxalyl-115,21-dihydroxy-4,17(20)- [trans]-pregnadien-3-one 21-trimethylacetate.

e) Treating 1 15,21-dihydroxy-4, 17 (20) [trans]-pregnadien-S-one with potassium ethoxide and methyl oxalate produced the potassium enolate of 2-methoxyoxalyl- 115,21-dihydroxy'4, 17 (2Q) -[trans]-pregnadien-3-one.

In the same manner as shown in Examples 1 and 2 treating other 21-esters of 115,21-dihydroxy-4,17(20)- [transJ-pregnadien-B-one with a lower-alkyl oxalate in the presence of a base such as sodium, potassium, lithium, methoxide, ethoxide, propoxide, butoxide, or the like, produces the corresponding alkali metal enolates of the 2 lower alkyl 115,21-dihydroxy-4,17(20)-[trans]- pregnadien-3-one 2l-acylates. Such produced alkali metal enolat es of 2-alkoxyoxalyl-1 15,21-dihydroxy-4,17- 20) -[trans] -pregnadien-3-one- 2l-acylates comprise: the sodium, potassium and lithium enolate of Z-butoxyoxalyl 115,21 dihydroxy-4,17(20)-[transJ-pregnadien- 3-one Zl-acetate, 2-amyloxyoxalyl-l15,21dihydroxy- 4,17 (20) [trans] -pregnadien-3-one 2 l-acetate, 2-hexyloxyoxalyl 115,21 dihydroxy 4,17(20) [trans]. pregnadien-3-one 21-acetate, 2-heptyloxyoxalylrl15,21-dihydroxy 4,17(20) [trans] pregnadien 3 one 21,- acetate, 2 octyloxyoxalyl 115,21 dihydroxy 4,17- (20)-[trans]-pregnadien-3-one 21-acetate; the sodium, potassium and lithium enolates of Z-methoxyoxalyl and 2 ethoxyoxalyl 115,21 dihydroxy-4,17(20)-[trans]- pregnadien-3-one 21-acylates wherein the acylate group is valerate, isovalerate, hexanoate, heptanoate, octanoate, -cyclopentylpropio-nate, phenylpropionate, anisate, dineopentylacetate, triethylacetate, salicylate, toluate, acid succinate, acid tartrate, acid maleate, cbloroacetate, dichloroacetate, trichloroacetate, brornoacetate, iodoacetate, fluoroacetate, trifluoroacetate, orthorbromobenzoate, meta-nitrobenzoate, toluenesulfonate, benzenesulfonate, or the like.

EXAMPLE 3 Z-ethbxywgalyl-2-methyl-l15,21-dihydr xy-4,1 7 (2 0) [trans] -pr egnadien-3-one 21- aceiate' A mixture of 32 grams of the sodium enolate of 2- ethoxyoxalyl 115,21 dihydroxy 4,17(20) [translpregnadien-3-one 21-acetate, 35 grams of potassium carbonate and seventy milliliters of methyl iodide, dissolved in one liter of acetone, were refluxed for a period of eighteen hours. The mixture was then concentrated to about 750 milliliters of volumn, cooled and filtered. The potassium carbonate filter cake was washed with four ZSO-millilfer portions of hot acetone. The combined acetone solution wasdistilled to dryness at reduced pressure to give 2-ethoxyoxalyl-2-methyl-l15,2l-dihydroxy- 14 ,1 9.0) an u esnad e 3 o e zhace a e thex-yo a y 2 m h 5 h r xy 2 a etoxy-4,l7(20)-pregnadien-3--one). The infrared spectrum of 2-ethoxyoxalyl-2+methyl115,21-dihydroxy-4,l7- (20)-[transl-pregnadien-3 one 21-acetate in chloroform corresponded to the proposed structure.

E A P E 4 In the manner shown in Example 3,

'(a) Treating the sodium enolate of Lethoxyoxalyll15,21-dihydroxy-4,17(20).-[trans]-pregnadien-3:one 2 1- propionate with methyl iodide in the presence of sodium carbonate produced 2-ethoxyoxalyl-2rme'thyl-115, 21-dihydroxy14,17 (20) [trans] -,pregnadien-3-one 21-propionate. V

(b) Treating the potassium enolate of Z-methoxyoxalyl 115,21 dihydroxy:4,;17 (20) [transl-pregnadiem S-one' ZI-ben o-ate with methyl iodide in the presence of sodium carbonate produced 2emethoxyoxalylr2rmethyl- 1 15,2 1-dihydroxy-4, 1 7 (2.0 [trans] -pregnadier t-3v-one 2 1- ben'zoate.

(c) Treating the potassium enolate of Z-ethoxyoxalyL 1 15,21-dihydroxy-4,17( 20)-[trans1-pregnadien-3-one 21- phenylacetate with methyl iodide in the presence of soium ar at Pr du d i 0XYX 1Y l Y 11 21-dihydroxy-4,l7(20)-[trans] pregnadien-3 one 21- phenylacetate.

(d) Treating the lithium enolate of 2-butoxyoxalyl 115,21-dihydroxy-4, 17 (20)- [trans] -pregnadien-3-one 2 1- acetate with methyl iodide in the presence of sodium carbonate produced 2-butoxyoxalyl-2-methyl-115,21-dihydroxy-4, 1 7 2O trans] :pregnadiemS-one 21-acetate.

' (e) Treating the sodium enolate of Z-ethoxyoxalyl- 115,21 dihydroxy 4,17(20) [translapregnadien-fl-one with butyl bromide in the presence of potassium care bonate produced 2 ethoxyoxalyl-2-but-yl-115,2Ldihydroxy-4, 17 (20) [trans] -pregnadi en-3-o ne. Z

(f) Treating the sodium enolate of 2-ethoxyoxalyl- 115,21:dihydroxy4,17(20)-[transJ-pregnadien-El-one 21- acetate with ethyl iodide in the presence of potassium carbonate produced 2 ethoxyoxalyl 2-ethyl-'l l5, 2 l-dihydroxy-4, l 7 20 [trans] -pregnadien,3-one 21-acetate.

(g) Treating the sodium enolate of 2ethoxyoxalyl 115,21-dihydroxy-4,17 (20)'- [trans] -pregnadien-3-one 21- acetate with propyl idodie in the presence of potassium carbonate produced 2 ethoxyoxalyl 2-propyl-115,2;l-'

dihydroxyt, 17 (20) [trans] pregnad ien-3-one 2 l-acetate.

(h) Treating the sodium enolate of 2-ethoxyoxalyl- 1 15,21-dihydroxy-4,17 (20) -[trans]-pregr 1adien-3-one 21- acetate with pentyl iodide in the presence of potassium carbonate produced 2-ethoxyoxalyl-2epentyl-115,2l-dihydroxy-4,17(20)-[trans]-pregnadien-31one 2 l-acetate.

(i) Treating the sodium enolate of 2-.ethoxyoxalyl- 115,21-dii1ydroxy-4, 17(20) [trans] -pregnaclien=3-one 21,- acetate with hexyl chloride in the presence of potassium carbonate produced 2-ethoxyoxalyl-2-hexyl-115,21-dihydroxy-4, 1 7 20) [trans] -pregnadien-3 -one 21-acetate.

(j) Treating the sodium enolate of 2-ethoxyoxalyl- 1 15,21-dihydroxy-4,17 (20) [trans] -pregnadi en-3-one 21- acetate with heptyl iodide in the presence of potassium carbonate produced 2-ethoxyoxalyl-2-heptyl-115,21-dihydroxy-4,17(20)-[trans]-pregnadien-3-one 21-acetate.

(k) Treating the sodium enolate of Z-ethoxyoxalyl- 115,21-dihydroxy-4,l7 (20)- [trans] -pregnadien-3-one 21- acetate with octyl iodide in the presence of potassium carbonate produced Z-ethoxyoxalyl-Z-octyl-l15,21-dihy droxy-4, 17(20) [trans -pregnadien-3 -one 21-acetate.

Z) Treating the sodium enolate of 'Z-ethoxyoxalyl- 1 15,2 1-dihydroxy-4, 17 (20) [trans] -pregnadien-3-one 21- acetate with benzyl iodide in the presence of potassium carbonate produced 2-ethoxyoxalyl-2 -benzyl'-115,2l-dihy drox -4, 17 (20) [transJ-pregnadien-3-one 21-acetate.

(m) Treating the sodium enolate of Z-ethoxyoxalyl 1 l5,2l-dihydroxy-s4, 17 (20) [trans] -pregna,dien-3V-one 21- acetate with phenyl iodide in the presence 91 59%5511113;

155 carbonate produced 2-ethoxyoxalyl-2-phenyl-115,21-dihydroxy-4, 17 (20) [trans] -pregnadien-3-one 21-acetate.

In the same manner as shown in Examples 3 and 4, treating an alkali metal enolate of a 2-lower-alkyloxyoxalyl 115,2l-dihydroxy-4,17(20)-[trans]-pregnadien-3 one 2l-acylates with a lower-alkyl halide preferably a lower-alkyl halide wherein the alkyl group has from one to eight carbon atoms and the halogen an atomic weight between 34 and 130 preferably in the presence of a catalyst such as sodium or potassium carbonate produces the corresponding 2 lower-alkoxyoxalyl-Z-alkyl-115,21-dihydroxy-4,l7(20)-[trans]-pregnadien-3-one 21-acylates illustratively those 2-lower-alkoxyoxalyl2-alkyl-115,21-dihydroxy 4,17(20)-[trans]-pregnadien-3-one 21-acylates wherein the alkoxy group is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or the like, the alkyl group is methyl, ethyl, propyl, pentyl, hexyl, heptyl, octyl, benzyl, phenyl, or the like, and the acyl group of the acylate is acetyl, propionyl, butyryl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl, benzoyl, toluenesultonyl, anisoyl, gallyl, toluyl, chloroacetyl, dichloroacetyl, or the like.

EXAMPLE 5 2-methyl-115,2I-dihydr0xy-4,l 7 20) trans] -pregnad im- 3 -one 21 -acetate Thirty grams of 2-ethoxyoxalyl-2-methyl-l15,21-dihydroxy-4,l7(20)-[transl-pregnadien-3-one 21-acetate was dissolved in 350 milliliters of methanol and thereto was added eighteen milliliters of sodium methoxide solution (25 percent solution of sodium methoxide in methanol). The reaction mixture thus obtained was stirred for a pe riod of five hours and then allowed to stand overnight (eighteen hours) at room temperature (22 to 25 degrees centigrade). At the end of this period, the solution Was extracted with five ZOO-mi liliter portions of methylene chloride. The combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, filtered through anhydrous sodium sulfate and concentrated to dryness at reduced pressure. The residue thus obtained was Z-methyl-ll5,21-dihydroxy-4,17-(20)- [trans]-pregnadien-3-one.

The thus obtained 2 methyl 115,21 dihydroxy- 4,l7(20)-[trans]-pregnadien-3-one was dissolved in seventy milliliters of pyridine and thereto was added 100 milliters of acetic anhydride. The mixture was maintained at room temperature, about 22 to 25 degrees centigrade, for a period of eighteen hours. Thereafter the mixture was poured into ice Water and extracted with methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate, concentrated to dryness at reduced pressure and the remaining crude residue was chromatographed over 1140 grams of Florisil magnesium Fractions 4-8 were combined and evaporated. The thus obtained crystalline material was recrystallized from ethyl acetate-Skellysolve hexane to give 2.47 grams of 2- methyl l15,21-dihydroxy-4,l7(20){translpregnadied 3-one 21-acetate (2 methyl 115 -hydrox -21-ac i 4,17(2t )-[trans]-prcgnadien-3-one) of meltin point 63 to' 171 degrees centigrade, [a] (acetone) plus 128 degrees.

Analysis.-Calcd. for C I-1 0 C, 74.57; H, 8.87.

Found: C, 74.27; H, 9.27.

EXAMPLE 6 2 -methyl-] 15,21 -dihydr0xy-4,1 7(20 [trans] -pregnadien- 3-0ne In the manner shown in Example 5, treating Z-ethoxyoxalyl 2 methyl 115,2l-dihydroxy-4,l7(20)-[trans]- pregnadien-3-one 2l-propionate with potassium ethoxide in ethanol solution resulted in Z-methyl-l15,21-dihydroxy- 4,17(20)-[transl-pregnadien-3-one.

Hydrolyzing in the manner shown in Examples 5 and 6, the 2 methoxyoxalyl 2 methyl 115,21-dihydroxy- 4,17(20)-[transl-pregnadien-3-one 21-benzoate of Example 4b, 2 ethoxyoxalyl 2 methyl-115,21-dihydroxy- 4,17(20)-[transl-pregnadien-3-one 21-phenylacetate of Example 40, and the Z-butoxyoxalyl-Z-methyl-l15,21-dihydroxy-4,l7(20)-[trans]-pregnadien-3-one 2l-acetate of Example 4d, with sodium ethoxide or sodium methoxide in methanol or ethanol solution or with other bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, or the like in aqueous alcoholic solution yielded 2 methyl 115,21 dihydroxy-4,17(20)-[transl-pregnadien-3-one.

EXAMPLE 7 Hydrolyzing in the manner shown in Example 5 with potassium methoxide in ethanol:

(a) 2 ethoxyoxalyl- 2- butyl 115,21 dihydroxy- 4,l7(20)-[transl-pregnadien-it-one yielded 2-butyl-11, 52l-dihydroxy-4, 17 (20 [trans] -pregnadien-3-one.

(b) 2 ethoxyoxalyl 2 ethyl 115,21 dihydroxy- 4,17(20)-[transl-pregnadien-3-one 21-acetate yielded 2- ethyl ll5,21-dihydroxy-4,17-(20)-[trans]-pregnadien-3- one;

(0) 2 ethoxyoxalyl 2 propyl 115,21 dihydroxy- 4,17(20)-[transl-pregnadien-B-one yielded 2-propyl-115, 2 l -dihydroxy-4, 1 7 20) [trans l -pregnadien-3-one.

(d) 2 ethoxyoxalyl 2 pentyl 115,21 dihydroxy- 4,17(20)-[transJ-pregnadien-3-one 21-acetate yielded 2- pentyl 115,21-dihydroxy-4,17(20) -[trans]-pregnadien-3- one.

(e) 2 ethoxyoxalyl 2 hexyl 115,21 dihydroxy- 4,17(20)-[trans]-pregnadien-3-one 21-acetate yielded 2- hexyl l15,21-dihydroxy-4,l7(20)-[transl-pregnadien-3- one.

(1) 2 ethoxyoxalyl 2 heptyl 115,21 dihydroxy- 4,17(20)-[transl-pregnadien-S-one 21-acetate yielded 2- heptyl 1l5,21-dihydroxy-4,17(20)-[trans]-pregnadien-3- one.

(g) 2 ethoxyoxalyl 2 octyl 115,21 dihydroxy- 4,17(20)-[transl-pregnadien-3-one 21-acetate yielded 2- octyl 115,21-dihydroxy-4,17(20)-[trans]-pregnadien-3- one.

(11) 2 ethoxyoxalyl 2 benzyl 115,21 dihydroxy- 4,17(20)-[trans]-pregnadien-3-one 21-acetate yielded 2- benzyl-l 15,21-dihydroxy-4,17(20)-pregnadien3-one.

(i) 2 ethoxyoxalyl 2 phenyl 115,21 dihydroxy- 4,17(20) [trans] pregnadien 3 one 21 acetate yielded 2 phenyl 115,21 dihydroxy 4,17(20)- [trans]-pregnadien-3-one.

In the same manner as shown in Example 5, the 21- alcohols of 2 lower alkyl 115,21 dihydroxy- 4,17(20)-[trans]-pregnadien-3-one of Examples 5, 6, and 7 can be esterified to give the corresponding 21-esters. Esterification is usually carried out in the manner shown in Example 5, using a solvent such as pyridine or a neutral solvent such as ether, benzene, toluene, or the like, and an esterification reagent such as an anhydride or a chloride or bromide of an organic carboxylic acid respectively of a hydrocarbon carboxylic acid. The anhydrides and halides of organic carboxylic acids or hydrocarbon carboxylic acids useful in the esterification comprise those from one to eight carbon atoms in particular, but those containing up to twelve carbon atoms such as, for example, lauryl or dineopentylacetyl bromide or chloride are utilizable. The thus obtained 2-lower-alkyl-1l5,21-

17 dihydroxy 4,17(20) [trans] pregnadien 3 ones 2'1-acylates comprise the 2-1-acetate, propionate, cyclopentylpropionate, butyrate, i'sobutyrate', valerate, isovalcrate, hexanoate, heptanoate, octanoate, phenylacetate, benzoate, toluate, trimethylacetate, dineop'entylacetate, triethylacetate, a chloro, bromo and iodo. and; fluoroacetate, trichloroandtrifluoroacetate, toluenesulfonate, benzenesulfonate, nictonate; 2.-furoate, and othert acid-estersof. 2-lower-alkyl-l 15,2 1 dihydroxy-4', l 7 (20) [trans] -pregnadien-B-one wherein the. lower-alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl, phenyl, benzyl, or the like.-

EXAMPLE" 8 A solution was prepared containing2;47 grams of 2- methyl 115,21 dihydroxy 4,1 7(20)'-- [transl' pregnadien-S-one Z'l-acetate, dissolved in- 100 milliliters tertiarybutyl alcohol, fifteen milliliters of pyridine and 1.78 grams of osmium tetroxide. The solution was stirred at room temperature at about 23 degrees centigrade for thirty minutes and then allowed to stand overnight at room temperature (22 to' 25' degrees-centigrade). To this solutionwas then added 100milliliters-of water. Thereupon sulfur dioxide gas was bubbled through the mixture for a period of ten-minutes; Thereafteran additional 100 milliliters of'water were added and the solutionwas extracted with 2'50milliliters ofmethylene chloa ride The methylenechloride extracts werewashed, once with: water, once with four percent aqueous sodium bicarbonate, filtered through anhydrous sodium sulfate and concentrated to dryness at reduced pressure; The thus obtained product was recrystallized from ethyl acetate- Skellysolve B hexanes to give pure 2-methyl-1lp,17 x,20[3, 3l-tetrahydroxyr4epregnen 3Tone 21-acetate (Z-methyl Reichsteins substance; E. 21-acetate) of melting point 199 to 203 and rotation [ul of:plus:120 degrees (acetone).

Analysis.Calcd. for C H O' C, 68.54; H, 8L63'. Found: C,.68.44; H, 8.69.

EXAMPLE. 9

In the same manner as shown in: Example 8, treating with osmium tetroxide in tertiary butyl alcohol and pyridine:

(a) 2 methyl 115,21 dihydroxy 4,17(20)- [transl-pregnadien-Smne and hydrolyzing the thus;produced 17(20)-osmate with water and sulfur dioxide yielded 2 methyl 11fi,17a,20;8-,21- tetrahydroxy 4-- pregnen-3-one.

(b) 2 ethyl 1113,21 --dihydroxy 4,17(20) [trans]- pregnadien-B-one 21-acetate and hydrolyzing. the thus produced 17 (20)-osmate with water and sulfur dioxide yielded 2 ethyl 1113,170c,20fi,21 -tetrahydroxy 4- pregnen-3-one 21-acetate.

(c) 2 propyl 115,21 dihydroxy-4,17( 20)'-[transJ pregnadien-3-one 21-acetate and hydrolyzing the-thus produced 17(20)-osmate with: water and sulfur. dioxide yielded 2 propyl- 1 lfl,'17a,20 3,21- tetrahydroxy 4- pregnen-B-one 21-acetate.

(d) 2 isopropyl 1-1fi,21 dihydroxy 4,17(20)- [trans]-pregnadien-3-one ZI-acetate. and hydrolyzingv the thus produced l7(20)-osmate: withv water and sulfur dioxide yielded 2-isopropyl-11,8,17d,20fl,2I-tetrahydroxy-4- pregnen-3-one 21-acetate.

(e) 2 butyl 1,8,21 dihydroxy 4,17(20) [trans]- pregnadien-3-one 21-acetate and. hydrolyzing the thus.

produced 17(20)-osmate with water and sulfur dioxide yielded 2-butyl-l1B,l7d,20/3,21-tetrahydroxy-4-pregnen-3- one 21-acetate.

(f) 2 pentyl 115,21- dihydroxy 4,17 (20) [translpregnadien-3'-one 21-acetate andhydrolyzing the thus produced 17(20)-osmate with water andsulfur dioxide 18 yielded 2-penty1-1 1,8,170:,20 5321-tetrahydroxy-4-pregnene 370116 21-acetate.

(g) 2 hexyl -'11,B,21 dihydroxy- 4,17(20) translpregnadien-3 one ZI-acetate and hydrolyzing, the thus produced 17 (-20)-osmate with. water and sulfur dioxide yielded 2- hexy1 11,8,17'a,20,8,2l-tetrahydroxy-4-pregnen:3- one 21-acetate.

(h) 2 heptyl 115,21 dihydroxy-4,17(20)-[trans]- pregnadien-3=one- 21.-acetate and hydrolyzing the thus produced 17'(20)-0smate with: water. andsulfur' dioxide yielded- 2-heptyl-1 15,17ix,20 8,21-tetrahydroxy 4=pregpen+ 3-one 21-acetate;

(i) 2 octyl 11,8,21 -dihydroxy --4,17(20)--- [trans]: pregnadien-3-one 2l-acetate and: hydrolyzing, the" thus produced 17 (20)-osmate withwater. and sulfur dioxide yielded 2-octyl-1 1p, 17u,20,8,21-tetrahydroxy-4-pregnen13 one 21-acetate. I

(j) 2- benzyl 11 8,21 dihydroxy 4,17(20) -'[trans]- pregnadien-B-one. 21 -acetate and, hydrolyzing the. thus produced 17(20) -osmatewithvwater. andsulfur, dioxide yielded 2-benzyl-l1,8,172x,20,8,21rtetrahydroxyA-pregnen- 3-one 21i-acetate.

(k) 2 phenyl 1118,21- dihydroxy4,17(20)-[trans]: pregnadien-3-one 21l-acetate and hydrolyzing the, thus produced 1'7(20)-osmate with. water and sulfur dioxide yielded 2-phenyl-1'1fl,17a,20,8,2l-tetrahydrnxy 4pregnene 3-one 21-acetate.

(l) 21- methyl 115,211- dihydroxy-4,17(20).-[trans]- pregnadien-3 o-ne 2,1"-propionate andhydrolyzing the thus produced 17(2"O)-osmate with water and' sulfur dioxide yielded Z-rnethyhl'lfl,172x,20,8,21rtetrahydroxy 4 pregnen- 3-one 2l-propionate.

(m) 2 methyl 11,B,'21L dihydroxy-4,17(20)-[trans] pregnadien-3 one Zl-benzoate and hydrolyzing the thus produced 17(20) -osmate with water. and sulfur dioxide ('n') 2 methyl- 11,8,2'1 dihydroxy-4,17(20)-[trans] pregn'adien-3 one ZL-phenylacetate' and hydrolyzing the thus produced.1 7(20,)'-osmate with water andsulfurdioxide yielded Z-methyl-l1p,1=7a,20fi;21'-tetrahydroxy=4= pregnen-3-one 2'1'-phenylacetate;

(0.) 2- methyl 115,21 dihydroxy-4,17(20)}[transil pregnadien-B-one ZI-trimethylacetate and hydrolyzing the thus produced 1'7"(2'0)-osm'ate with water and sulfur di -1 oxide yielded Z methyl-l'l',8';l7 203)l'-tetrahydroxy 4 pregnen-K-One ZI-trimethylacetate;

In the same manner as' shown in Example 9other' 2"- lower-alkyl- 115,21 dihydroxy 4,17(20) [translpregnadien-B-ones-may beiptreated' with osmium tetroxidb and tertiary butyl alcoholin pyridine ondioxane and pyridine to give the corresponding"1'7(20)'-osmate, which with water and sulfur dioxide (sulfurous' acid) are" de= composed to give the corresponding; 2 lower5alliyl llfl;l7a,20)3,2l tetrahydrox-y 4'- preg nene- 3'--one: 21'- acylates. Thus obtained more important acylates include the 2 methyl 115,17a,20fi;21"- tetrahydroxy=4 pregnen= 3-0ne 21-acylates wherein the 21acylate can be butyrate, isobutyrate,,. valerate,, isovalerate, hexanoate, heptanoate,

' octanoate, phenylpropionate,toluate cinnamate, lactate,

acid tartrate, dihydrogencitrate, chloroacetate, bromoacetate, fiuoroa'cetate, iodo'acet'ate, dichloroa'cetate, di-

neope'ntyla'cetate, trietliylace'tate or? the like.

EXAMBLE; 1.0

A mixture of two: grams of 2-methyl-1'1fi,l72x,20,B;21= tetra-hydroxy 4-pregnen=3 one' 21-acetate, 25milliliters of pyridine and 25" milliliters of acetic anlrydride' was. maintained at room temperature for a periodiofitwentyhours; thereafter'the'. reaction mixture was pouredinto icewat'er to give. a precipitate which was recovered by filtration; The thus obtained: crude crystalline material was re crystallized from ethyl acetate Skellysolve B" hexanes t'o give pure 2 methyl 1113,17oz,20}3,21 tetrahydroxy-4 pregnen 3 one 20,21 diacetate 2 methyl 115,170:- dihydroxy-20fi,21-diacetoxy-4-pregnen-3-one of melting point 221-223 degrees centigrade; rotation [@1 plus 180 degrees (acetone).

Analysis.Calcd. for C H O C, 67.51; H, 8.28. Found: C, 67.53; H, 8.19.

EXAMPLE 11 In the same manner as shown in Example 10:

(a) 2 methyl 11 3,l7tx,20;3,21 tetrahydroxy 4- pregnen-3-one 21-propionate was reacted with propionic anhydride in pyridine to give 2-methyl-11,8,17a,20p,21- tetrahydroxy-4-pregnen 3-one 205,21-dipropionate.

(b) 2 methyl 11B,17a,20 8,2l tetrahydroxy 4- pregnen-3-one 21-benzoate was reacted with benzoyl chloride in pyridine to give 2-methyl-1l,8,17a,20;3,2ltetrahydroxy-4-pregnene-3-one 20,8,21-dibenzoate.

I (c) 2 methyl 11;8,17u,20fi,2l tetrahydroxy 4- pregnen-3-one 2l-phenylacetate was reacted with phenyl acetyl bromide in pyridine to give 2-methyl-llfi,l7a,20 8, 21-tetrahydroxy-4-pregnen-3-one 203,21-diphenylacetate.

(d) 2 methyl llfi,17rx,20fi,2l tetrahydroxy 4- pregnen-3-one 21-toluenesulfonate was reacted with toluenesulfonyl chloride in pyridine to give 2-methyl- 20,8,21-ditoluenesulfonate.

(e) 2 ethyl l1fi,17oc,20[3,21 tetrahydroxy 4- pregnen-3-one 2l-acetate was reacted with benzoyl chloride to give 2 ethyl 115,17u,20fi,21 tetrahydroxy-4- pregnen-3-one ZOB-benzoate, 21-acetate.

(f) 2 propyl 11;8,17a,20/3,21 tetrahydroxy-4-pregnen-3-one 21-acetate was reacted with butyryl chloride to give 2-propyl-11,8,1711,2052l-tetrahydroxy-4-pregnen- 3-one ZOB-butyrate, 21-acetate.

(g) 2 benzyl 11B,l7a,20}3,21 tetrahydroxy-4-pregnen-3-one 21-acetate was reacted with valeryl chloride to give 2 benzyl 1l/3,17oz,20fl,2l tetrahydroxy 4-pregnen-3-one ZOfl-valerate, 21-acetate.

In the same manner as given in Examples 10 and 11 other 2 lower-alkyl l15,17u,20,8,21 tetrahydroxy 4- pregnen-3-one 205,21-diacylates are obtained by esterif ing the 2-lower-alkyl-11fi,17a,205,2l-tetrahydroxy-4-pregnen-3-one 21-acylates, dissolved in pyridine or in a neutral solventsuch as benzene, toluene, ether or the like, with an acylating agent such as a halide or anhydride of an organic carboxylic acid, preferably hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive. Such 2-lower-alkyl-11/3,17a, 20,9,21-tetrahydroxy-4-pregnen-3-one 205,21-diacylates include: 2 butyl 11,8,17u,20,8,21 tetrahydroxy 4-pregnen'3-one ZO S-(Z-furoate), 2l-acetate, 2-benzyl-115,17ct, 2018,1 .1-tetrahydroxy-4-pregnen-3-one ZOQ-nicotinate, 21- acetate, 2-methyl-1 1 ,8,17a,20;8,2l-tetrahydroxy-4-pregnen- 3-one ZOfi-acetate, ZI-trimethylacetate, 2-methyl-l1;3,17a, 205,21-tetrahydroxy-4-pregnen-3-one 20 3-propionate, 21- dineopentylacetate and the like.

EXAMPLE 12 Z-methyl-I 7a,2 018,21 -trihydrxy-4-pregnene- 3,11-di0ne 20,21-diacetate A solution of 462.5 milligrams of 2-methyl-l1fi,17u, 205,21-tetrahydroxy-4-pregnen-3-one 20,2l-diacetate in thirty milliliters of acetone and two milliliters of water was mixed with 311 milligrams of N-bromoacetamide. After stirring for three hours the reaction mixture was poured into thirty milliliters of water containing 600 milligrams of sodium sulfite and stirred for a period of one hour. The acetone was distilled at reduced pressure and the solution was extracted with methylene chloride. Evaporation of the solvent gave an oil which could not be recrystallized but the infrared spectrum was in agreement with the proposed structure for 2-methyl l7a,20B,21 trihydroxy-4-pregnene-3,1l-dione 20,21-diacetate. Rotation was [0:1 plus 130 degrees (acetone).

20' V ExAMPLn-13 2 methyl l7oc,20]3,21 t rihya'roxy 4 pregnene 3,11- dione 205,21 diacetate from 11 3,21 'dihydroxy 4,17(20)- [cis]-pregnadien-3-one 21 -acetate (a) 2 glyoxalylation of 1113 hydroxy 21 acetoxy- 4,17(20)-[cis]-pregnadien-3-one.A solution of 18.62 grams (0.05 mole) of llfi-hydroxy-21-acetoxy-4,17(20)- pregnadien-B-one was prepared in 300 milliliters of dry tertiary butyl alcohol by heating the mixture at seventy degrees centigrade. The solution was cooled to 55 degrees centigrade and to the stirred solution, protected from atmospheric oxygen by bubbling nitrogen therethrough, was added 11.5 grams (0.10 mole) of methyl oxalate followed by a solution of 4.05 grams (0.075 mole) ofsodium methoxide, dissolved in sixteen milli liters of methanol. A thick, pale yellow precipitate soon appeared. Stirring was continued for ten minutes and the mixture was then diluted with 300 milliliters of anhydrous ether. Stirring was continued for an additional fifteen minutes and the mixture then filtered. The pale yellow-green precipitate was washed and dried at room temperature (2225 degrees centigrade) in a vacuum. The yield of about 24 grams of precipitate consisted primarily of a sodium enolate of 2-methoxyoxalyl-1lB-hydroxy-21-acetoxy-4,17 (20) [cis]-pregnadien-3-one.

The precipitate was dissolved in 250 milliliters of water and the solution acidified with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried. There was thus obtained 18.71 grams of an amorphous powder consisting essentially of Z-methoxyoxalyl-l1 8-hydroxy-21-acetoxy- 4,l7(20)-[cis]-pregnadien-3-one which melted at eighty to degrees centigrade and which gave a positive redbrown ferric chloride test.

(11) 2-methyl-2-mezh0xy0xalyI-1Jfi-hydmxy-ZI-acetoxy- 4,17(20)-[cisl-pregnadien-3-0ne.A mixture of 4.70 grams of crude 2-methoxyoxalyl-11,B-hydroxy-4,17(20)- pregnadien-3-one, obtained according to the method of Example 1, ten grams of anhydrous potassium carbonate, fifteen milliliters of methyl iodide and milliliters of acetone were stirred at about 25 degrees centigrade for forty hours. Water was then added and the mixture extracted thoroughly with methylene chloride. The extract was washed with water, dried and the solvent distilled to leave a glassy residue of 2-methyl-2-methoxyoxalyl 1113 hydroxy-21-acetoxy-4,l7(20)-pregnadien-3- one.

(c) Z-methylJI 5,21-dz'hydr0xy-4J 7(20) [cis] pregnadien-3-one.-The glassy residue of crude 2-methyl-2- methoxyoxalyl-1 lfi-hydroxy-Z l -acetoxy-4, 17 (20 -pregnadien-3-one, obtained according to the method described above, was dissolved in fifty milliliters of methanol to which was then added three milliliters of a 25 percent solution of sodium methoxide in methanol. The now red solution was stirred for a period of two hours at about 25 degrees centigrade. The mixture was then diluted with about 200 milliliters'of water and extracted thoroughly with methylene chloride. The combined methylene chloride extracts were washed with water, dried and the solvent then distilled therefrom, leaving a steroidal residue of 2-methyl-l15,2l-dihydroxy-4,17(20)- [cisl-pregnadien-S-one. The thus-produced Z-methyl- 11B,2l-dihydroxy-4,l7(20) [cis] pregnadien-S-one is purified by chromatography over Florisil synthetic magnesium silicate developed with Skellysolve B hexanes containing increasing proportions of acetone.

(d) 2-methyl-1Ifi-hydroxy-21-acetoxy-4,17(20){visipregnadien-3-0ne.The crude residue obtained from the reversal reaction was dissolved in a mixture of ten milliliters of acetic anhydride and ten milliliters of dry pyridine. The mixture was maintained at about 25 degrees centigrade for about sixteen hours. The excess acetic anhydride was then decomposed with ice water and the resulting gummy precipitatewas extracted with benzene.

assesse The b'enzerie solution waswashed with; cold, dilute hydro,- chloric acid; cold aqueous sodium bicarbonate, water, and'then dried. The dried benzene solution was poured over a chromatographic column of 100 grams of Florisil synthetic magnesium silicate. The column was developed with 1350 milliliters of Skellysolve B hexane hydrocarbons containing five percent acetone followed by 750 milliliters of Skellysolve B plus 7.5 percent acetone and then 150 milliliters of acetone. The eluates were collected in 150 milliliter fractions. Eluate fractions 4 to 8 contained a total of. 1.71 grams, a yield of 44 percent, calculated on the starting Z-methoxyoxalyl-l15,21-dihydnoxy-4,17(20)-pregnadien-3-one, of crystalline 2-methyl-llfi-hydroxy 21 acetoxy-4,17(20)-pregnadien-3ronet Recrystallization of this product gave 2-methyl-11fi-hydroxy-21-acetoxy-4,17(20)-pregnadien-3-one melting at 182. to 184.5 degrees centigrade, having an [rd of plus 145 degreesin chloroform, an ultraviolet absorption of 15;,02'5'millimicrons and the analysis below.

Analysis.Calcd. for C H O C, 74.57; H, 8.87. Found: C, 74.32; H, 8.79.

(e) 2 methyl-21-hyzlr0xy-4,17(20)-[cis] pregnadz'ene- 3,11-dione 21-acetate.-A solution of 1.3 grams of 2- methyl 115,21 dihydroxy-4,17(20)-[cisJ-pregnadien-3- ne.21'-acetate in 120 milliliters of glacial acetic acid was prepared at atemperature of fifteen degrees centigrade. Thereto was added a solution of 260 milligrams of chromic acid in 0.5 milliliter of water. The temperature of the reaction mixture did not rise above eighteen degrees centigrade. The solution was stirred for a period of ten minutes; and: thenallowed to standfor another period of ten minutes. The crystalline cropwasprecipitated with the. addition of 600 milliliters of water yielding 1.21 grams (93 percent yield) of 2-methyl-2l-hydroxy- 4,17(21)) [cis] pregnadiene 3,11 dione 21 acetate of melting point 155-158 degrees.

(1), Z-methyl-l 711,20 -ep0xy 21 hydr0xy-4-pregnene- 3,11 di0ne' 21-acetate.-A mixture was, prepared at a temperature of about ten degrees centigrade containing 0.2 gram of 2-methyl-2lhydroxy-4,l7(20)-[cisl-pregnadiene-3,l1-dione 2l-acetate, ten milliliters of chloroform and one milliliter of peracetic acid. This mixture was maintained at about five degrees centigrade for a period of eighteen hours. The solution was thereupon diluted with fifty milliliters of methylene chloride, washed once with water and once with four percent aqueous: sodium bicarbonate solution, then water and dried over anhydrous sodium sulfate. Recrystallization of the crude product from acetone-Skellysolve B gave pure Z-methyl- 17e,20ot-epoxy-21-hydroxy-4-pregnene-3,1l-dione 21-acetate of melting point 181-to 188 degrees centigrade.

(g) ]70c,Z0/3,21 rrihydroxy-Z-methyl-4-pregnene-3 11- di'one 21-acetale.Three grams of 2-methyl'-17a,20ixepoxy-21-hydroxy-4-pregnene-3,1l-dione 21-acetate, dissolved in 150 milliliters of dioxane, was refluxed with ten milliliters of 3.5 normal sulfurous acid for a period of one; hour. Thereafter. the mixture was concentrated to about twenty milliliters of volume at reduced pressure, then diluted with 200 milliliters of methylene chloride and washed with water and aqueous four percent sodium bicarbonate. After filtration through anhydrous sodium sulfate, the solution was distilled todryness at reduced pressure giving 17a,'20,8,21-trihydroxy-2-methyl-4-pre nene-3,11-dione ZI-acetate with an infrared spectrum in chloroform which wasconsistent with that expected for The methylene chloride extracts were 22 washed with water, dried over anhydrous sodium sulfate and evaporated to give an oil having a rotation of [M of plus degrees (acetone).

Analysis.-Calcd. for C H O C, 67.86; H 788; Found: C, 67.64; H, 8.12.

EXAMPLE 14 Z-methyl-I 711,205,21-trihydr0xy-4-pregnene3,1 l-d'ione EXAMPLE 15.

2.-m"ethyl-1 15,1 7 a,20B,21 -zetrahydr0xy- 4 pregnen-3-0ne 21 -trimethylacetate One gram of Z-methyl-l1p;17a,20fi,2l tetrahydroxy 4 pregnen-3-one (Example 9a) was dissolved in ten milliliters of pyridine. Thereto was added one milliliter of trimethylacetyl chloride and the mixture was heated on the water bath for a period of three hours at. a temperature of forty to fifty degrees. Thereafter the. reaction mixture was poured into excess'cold water'- andextracted with methylene chloride. The methylenechloride-extracts wereiwashed'with dilute sodium bicarbonate, water, dried over anhydrous sodium sulfate and evaporated'togivethe crude trimethylacetate. The crude trimethylacetate was recrystallized from acetone andSkellysolve B hexahes to give pure 2-methyl-1'1 {3,17 a,20fl,21'-tetrahydroxy-4- pregnen-3-one 2'1-trimethylacetatea Treating 2 methyl-17a,20B,2'1-trihydroxy-4*pregnene- 3,11-dione with trimethylacetyl bromide asshown-in Example 15, produces 2-methyl-l7a,20[3,21-trihydroxy-4- pregnene-3 ,1 l-dione 21-trimethylacet'ate.

In the same manner other halides of sterically hindered acids such astriethylacetyl chloride, dineopentylacetyl' chloride or bromide or the like may be-used to selectivelyesterify the primary 21-hydroxylgroup without producing esters of the 20fi-hydroxyl group.

. EXAMPLE 16 Z-methylhydfocortisone 21 -trimethyl-lzcetate A mixture of one gram of Z-methyl-l1/8,17a,2013,21- tetrahydroxy-4-pregnen-3-one. 21-trimethylacetate,

method of Attenburrow et al., Journ. Chem. Soc., 1094' (1952), and 25 milliliters of methylene chloride-was refluxed for a period ofsix'hours. Thereafterthe reaction mixture was filtered, the precipitate washedvwith three five-milliliterv portions of methylene chloride: and the filtrate and washings combined and evaporated. '[Zhe thus obtained material was purified by repeated recrystallization from acetone and Skellysolve: B to give pure'2-.methyl-- 11,8;17a,21-trihydroxy-4-pregnene-3,20-dione 2l-trimethy acetate (Z-methylhydrocortisone 21-trimethyla'cetate).

EXAMPLE 17' Z-methylcortisone trimethylacetaze;

In the same manner as shown in Example 16, Z-methyl- 17m,20fi,2l-trihydroxy 4 pregnen-3',1l'-dione 21-trimethylacetate wasoxidized with manganesedioxide in.

methylene dichloride to give 2-methyl-17a,2l-dihydroxy 4-pregnene-3,1 1,20-trione 2.1 -triethylacetate.

In the manner of Examplcs.16 and 17, other estersof 2-methylhydrocortisone and 2 methyl'cortisone and other.

2'-lower-alkyl cortisone and hydrocortisone esters are pre pared by either oxidizing the 20p-hydro'xy group of" the one gram of manganese dioxide: freshly prepared by the.

Z-methyl-J 7u,20,8,21-trihydr0xy 4,9(11 p egrzadien-S- one 2018,21 -a'iacetaze (Z-methyl-l 7ot-hydr0xy-20fi,2]-diacetxy-4,9(11 pregnadien-3-one A mixture of one gram of 2-methyl-11fi,17e,20fl,21- tetrahydroXy-4-pregnen-3-one 205,21-diacetate, 6O milligrams of N-bromoacetamide and six milliliters of pyridine was stirred in the dark for a period of five minutes. The mixture was then cooled in an ice water bath and a stream of sulfur dioxide was directed under the surface of the stirred mixture until a negative potassium iodide-starch test was obtained. Fifty milliliters of water was then added to the mixture and the mixture was maintained at about five degrees centigrade for thirty minutes. The precipitated white solid was filtered, washed with water and dried under vacuum. After recrystallization from acetone there was obtained pure 2-methyl-17a,20p,21-trihydroXy-4,9(11)-pregnadiene-3 ,20-dione 20,21-diacetate. Using instead of the 20,21-diacetate of 2-methyll1,8,17a,20,6,2l-tetrahydroxy 4 pregnen-3-o-ne the dipropionate, the dibutylate, the dibenzylate and the like, the corresponding 2-methyl l7ot,20fi,21 trihydroxy- 4,9(11)-pregnadien-3-one 205,21-dipropionate, dibutylate, dibenzylate and the like is obtained.

Hydrolyzing in a nitrogen atmosphere with potassium carbonate in methanol or ethanol, 2-methyl-17a,20;8,21- trihydroxy 4,9(11) pregnadien-3-one 20,8,21-diacetate produces the corresponding free alcohol, Z-methyl- 17a,20/3,21-trihydr-oXy-4,9(11)-pregnadien-3-one.

Reesterification of 2-methyl-17u,20fi,2l-trihydroxy- 4,9(11)-pregnadien-3-one with anhydrides or halides of hydrocarbon carboxylic acid of a straight chain structure produces the corresponding diacylates. If hydrocarbon carboxylic acids are used which have sterically hindered groups such as trimethylacetyl chloride, triethylacetyl chloride, dineopentylacetyl bromide or the like, the corresponding 21-monoesters of 2-methyl-17a,20t3,21-trihydroXy-4,9( 11)-pregnadien-3-one are obtained.

EXAMPLE 19 In the manner shown in Example 18 treating a 2-loweralkyl 11;3,17a,20/8,2l tetrahydroxy-4-pregnen 3 one 20 3,21-diacylate with N-brornoacetamide in pyridine solution gives the corresponding 2-lower-alkyl-llfi-hypohalo- 17a,20 3,21-trihydroxy-4-pregnen-3-one 20/3,21-diacylate which when decomposed with sulfur dioxide gave the corresponding 2-lower-alkyl 17a,20fi,21 trihydroxy- 4,9(1l)-pregnadien-3-one 205,21-diacylate.

-In this manner from:

(a) 2 ethyl-11,8,17ot,20}3,21-tetrahydroxy-4-pregnen- 3-one ZOB-benzoate, 21-acetate was obtained 2-ethyl- 17u,20fl,21-trihydroxy 4,9(11) pregnadien-3-one 20B- benzoate, 21-acetate.

(b) 2 propyl-l113,17a,20{3,21-tetrahydr0Xy-4-pregnen- 3-one 20 8-butyrate, 21-acetate was obtained 2-propyl- 17a,20;6,21-trihydroxy 4,9(11) pregnadien-B-one 20B butyrate, 21-acetate.

(c) 2 benzyl-l15,17a,20,8,21-tetrahydroxy-4-pregnen 3-one 20fl-valerate, 2l-acetate was obtained 2-ethyl- 17a,2018,21-trihydroxy 4,9(11) pregnadien-3-one 20;8- valerate, 2l-acetate.

(d) 2 butyl- 11,3,17u,20,8,2l-tetrahydroxy-4-pregnen- 3-one 2018,21 dipropionate was obtained 2-butyl- 17a,20;8,21trihydroxy-4,9 1 1 -pregnadien-3-one 20 3,21- dipropionate.

(e) 2 heXyl-11p,17a,2O/3,21-tetrahydroXy-4-pregnen- 3-one 205,2l-diphenylpropionate was obtained 2-hexyl 1701,20631-trihydroxy-4,9( 1 1 )-pregnadien-3-one 20 9,21- diphenylpropionate.

24 (f) 2 octyl-llfl,17,20,B,21-tetrahydroXy-4-pregnen- 3 one 2013,21 dihexanoate was obtained 2 octyl- 17a,20;8,21-trihydroxy-4,9(11)-pregnadien-3-one 20,8,21- dihexanoate.

EXAMPLE 20 2-methyl-9a-br0m0-1 15,1 7a,20fi,21-tetrahydroxy-4- pregnen-3-0ne 205,21 -diacezate A solution of one gram of 2-methyl-l7a,20fi,21-trihydroxy-4,9(11)-pregnadien-3-one 20,3,21-diacetate, dissolved in forty milliliters of methylene chloride, was reacted with two milliliters of 71 percent perchloric acid in twenty milliliters of water and thereto was added 412 milligrams of N-bromoacetamide in milliliters of tertiary butyl alcohol. The solution was maintained at room temperature for a period of twenty minutes and then mixed with a solution of 0.50 gram of sodium sulfite in 24 milliliters of water. The mixture was distilled at reduced pressure and the residual solution became cloudy. The product was then precipitated by the addition of 200 milliliters of a mixture of ice and water. The white crystalline precipitate of Z-IIlEthYl-9OL-bl'OIHO-11fi, 17a,20;9,21-tetrahydroxy-4-pregnene-3,ZO-dione 2019,21-diacetate was filtered, washed with water and then dried at room temperature in a vacuum. Recrystallization from a mixture of acetone and Skellysolve B gave pure 2- methyl-9a-bromo-11,8,l7a,2Ofi,2l-tetrahydroxy 4 pregnen-3-one 20,8,21-diacetate (2-methyl-9a-bromo-11 3,17- dihydroxy-20B,2l-diacetoxy-4-pregnen-3-one) EXAMPLE 21 2-ethyl-9a-chl0ro-11 3,17a,20fl,21-tetrahydroxy-4- pregnen-3-0ne ZOB-berzzoate, 21 -acetate A mixture of one gram of 2-ethyl-l7ot,20fl,2l-trihydroxy-4 .9(1l)-pregnadien-3-one 20/3 benzoate, 21-ace tate, dissolved in fifty milliliters of methylene chloride, was reacted with a solution of two milliliters of 71 percent perchloric acid in ten milliliters of water and thereto was added N-chloro-succinimide in 100 milliliters of tertiary butyl alcohol. The solution was maintained at twenty degrees centigrade for a period of one hour then mixed with half a gram of sodium sulfite and twelve milliliters of water. The mixture was distilled at reduced pressure and the product precipitated with the addition of excess water. The white crystalline precipitate was filtered, washed, dried and recrystallized from acetone and Skellysolve B hexanes to give pure 2-ethyl-9achloro-l1B,17ot,205,2l-tetrahydroxy-4-pregnen-3-one 20 3- benzoate, 21-acetate (2-ethyl-9a-chloro-11,9,1704 dihydroxy-ZOfi-benzoxy-Z l -acetoxy-4-pregnen-3-one) EXAMPLE 22 In the same manner as shown in Examples 20 and 21, reacting 2-lower-alkyl-l7a,20fl,21 trihydroxy 4,9(l1)- pregnadien-3-one 20,8,21-diacylate in solution with a N- halo acid amide in the presence of acid to produce in situ a hypohalous acid yields the corresponding 2-loweralkyl-9cc-halo-115,17a,2(),8,21-tetrahydroxy-4 pregnen-3- one 20,13,21-diacylate wherein the halogen atom in the 9:1- position has an atomic weight between 34 and 130. Representative 9a-halo compounds thus obtained are: the 2- propyl-9a-halo-11/3,l7a,20p,21 tetrahydroxy 4-pregnen- 3-one ZOti-butyrate, ZI-acetate, the 2-benzyl-9ct-halo-11/9, 17a,20,8,21-tetrahydroxy-4-pregnen-3-one 20B valerate, 2 1-acetate, the 2-butyl-9ot-halo-l1B,17m,20fl,21 tetrahydroXy-4-pregnen-3-one 20,8,2l-dipropionate, the 2-hexyl- 9oc-halG-l1fi,l7cz,20fi, 21-tetrahydroxy-4 pregnen 3-one 206,2l-diphenylpropionate, the 2-octyl-9a-halo-11B,17m, 205,21-tetrahydroxy-4-pregnen-3-one 205,21-dioctanoate wherein the halo atom is bromo, chloro, or iodo.

A solution was prepared containing one half gram of 2- methyl-1113,17ot,20,6,21-tetrahydroXy-4-pregnen 3 one 25 205-,2l-diacetate dissolved in five milliliters of glacial aceticlacid. To this solution was added0.3'gram of chromic anhydride, dissolved in two milliliters of acetic acid, and one milliliter of water. The thus obtained solution was maintained at room temperature for a period of three hours. Thereafter one milliliter of methanol: Was-added, the solution was shaken andv poured into twenty milliliters of ice water. Sodium bicarbonate solution was added to neutralize the solution and the solution was then filtered to give a crude material which was recrystallized from acetone-Skellysolve B hexanes to give pure 2-methyl- 9a-bromo-17u,2OB,2l-trihydroxy-4-pregnene-3,11 dione 20,8,2l-diacetate.

EXAMPLE 24 2-ethyl-9ct-chl0r0-1 7 oc,2 0,8 ,2] -trihydrxy-4-pregnene- 3,11-di0ne ZOB-benzoate, 21 -acetate In the same manner as shown in Example 22 oxidizing 2-ethyl-9a-chloro-l118,17a,205,21- tetrahydroxy 4- pregnen-3-one ZOB-benzoate, 21-acetate with chromic acid in acetic acid solution produces the corresponding 2- ethyl-9wchloro-1711,2052l-trihydroxy 4-pregnene-3,11- dione ZOfi-benzoate, 21-acetate.

In the same manner as shown in Examples 22 and 23, other 2-lower-alkyl-l7'ct,20 3,2l-trihydroxy-4-pregnene 3, ll-dione 205,21-diacylates are prepared by oxidizing the corresponding 2-lower-alkyl 11p,17a,20;3,21 tetrahydroxy-4-pregnen-3-one 20,8,21 diacylates. Representative compounds thus obtained comprise the. 2-lower-alkyll7u,20fl,21-trihydroxy-4-pregnene-3,1l-dione 2OB,21 diacylates wherein the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, phenyl, benzyl or the like and wherein the acylate may be a diacetate, dipropionate, dibutyrate, dibenzoate, diphenylpropionate, diphenyla'cetate, dianisate, dinicotinate or the like or a mixed ester such as a 20,8-acetate, 2.1- propionate; 20,8-propion'ate, 21-benz'oate; 20,8-butyrate, 2l-hexanoate; 20fl-valerate, ZI-acetate and similar combinations.

Hydrolyzing 2 methyl 9a 'brom0-17a,2OB,2l-trihydroxy-4-pregnene-3,l l-dione 203,21-diacetate' with potassium carbonate in ethanol under nitrogen atmosphere as shown in Example 14 produces the corresponding free triol, 2-methyl-9a-bromo-17a,2OB,21-trihydroxy 4- pregnene-3,l1-dione.

In the same manner given in Example 15 selective esterification of 2-methyl-9u-bromo-17a,20;3,21-trihydroxy-4- pregnene-3,lldione with t'rimethylacetyl chloride, triethylacetyl chloride, dineopentylacetyl chloride or bromide, or with some similar halide of a hindered organic acid produced the corresponding 2-methyl-9ix-bromo-l7a, 20 6,21-trihydroxy-4-pregnene-3,ll-dione 21 trimethylacetate, triethylacetate, dineopentylacetate or the like.

In the manner shown in Example 16, oxidation of the 21-monoesters of 2 -methyl 9u-bromo-l7a,20B,2l-trihydroxy-4-pregnen-3,1l-dione ZI-trimethylacetate, t-riethylacetate of dineopentylacetate with manganese dioxide in a solvent such as hexane, heptane, Skellysolve B hexanes, methylene chloride, ethylene dichloride, chloroform, or

the like produces the corresponding 2-methyl-9a-bromo Y cortisone (2-methyl-9a-bromo 1704,21 dihydroxy 4- pregnene-3,1l,20-trione) trimethylacetate, triethylacetate, dineopentylacetate. In similar manner the chloro or iodo compounds of 2-lower-alkyl cortisone esters canbe made.

Similarly oxidizing 21-monoesters of 2-lower-alkyl-11B, 17a,20fi,21-tetrahydroxy-4-pregnen-3-ones with mangane'se dioxide in an organic solvent such as methylene chloride, ethylene chloride, hexane, heptane' or the like produces the corresponding 2-lower-alkyl-9a-halo-115,1704, 2l-trihydr0xy-4-pregnen-3,20-dione 2l-acylate wherein the lower-alkyl group, the halo group and the acrylate are defined as in thepreceding 2-lower-alkyl-9a-halocortis0ne acylates. In this manner 2-lower-alkyl-9'u-halohydrocortisone esters are produced such as for example 2-methy1-9abromohydrocortisone' ZI-tIimethyl-acetate, 2-methy1-9a- 2d chlorohydrocortisone. 21 trimethylacetate, 2- ethyl 9.1x bromohydrocortisone, ZI dineOpentyIacetate, or the like.

ExAMrLE 25 A mixture of 0.5 gram of 2-methyl 9'a-bromo-l113,170, 20B,2:1 tetrahydroxy 4-pregnen-3-one, 205,21- diacetate, 0.5 gram of anhydrous potassium acetate and twenty milliliters of acetone was heated at itsrefluxing temperature for a period of five hours. The coldmixture was thereuponpoured'iinto water and extracted with methylene chloride. The methylene chloride. extracts were dried over anhydrous sodium-sulfate andthen evaporated. The thus obtained residue was recrystallized from acetone and Skellysolve. B three times to give 2-metliyl-9B, l lfi epoxyl7ot,20,8,21strihydroxyA-pregnen-3-one 205,2l-diacetate.

EXAMPLE 26 one ZO-benzoate, 21 acetate In the same manner as shown in Example 25, 2-ethyl- 9a-chloro-l1,8,1711,20521-tetrahydroxy-4-pregnen-3 one 20 benzoate, 21 acetate was heatedqwith. anhydrous potassium-acetate' in acetone'solution to give 2-ethyl-9/3,11' 8- epoxy 17a,2OB,2l-trihydroxyl-pregnen-3-one ZQB-benzoate, 21-acetate.

Treating in the manner shown in Examples 25 and 26 2 --lower -alnyl 90641811341 fl;17bt,20fi,2 l-tetrahydroxy-lpregnen-S-one 20,2'l-diacylateswith anhydrous potassium acetate or anhydrous sodium acetate in an anhydrous solvent such as acetone, di-ox'ane tertiary butyl alcohol, chloroform or' the like at. a temperature between fifty degrees and the boiling point of the solvent produces the corresponding 2-l0wer-alkyl-9B,11.fi-epoxy-l7a,20 8,21rtrihydroxy-4-pregnen-3-one 20,2l-diacylate's. As starting compounds those 2-lower-alkyl-9u-halo-llB,17a,20 8,21- tetrahydroxy-4-pregnen-3-one 20,21-diacylates are useful -'in which the halo atom. is of atomic weight 34 to 130, wherein the alkyl' group contains from one toeight carbon atoms and wherein the acyl group of the acylate is of an organic carboxyl'ic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

EXAMPLE. 27

2 methyl 9a fluoro 11fi,17o:,20fl,21 telrahydroxy-4- pregnen-3-one 20,21 -diacetate (2z-methyl 9ot-fluoro-ll B, 1 7a-dihydroxy-20fi'j] -diacetoxy-4-pregnen-3 one) One gram of 2-methyl-9B,1l/i-ep-oxy-l7ot,20 8,2l-trihydroxy-4'pregnen-3-one 20,2l-diacetate, dissolved in fifty milliliters of methylene chloride, was treated with five milliliters of 48 percent hydrofluoric acid and 0.5 milliliter of 71 percent perchloric acid at room temperature. The mixture was stirred vigorously for a period of six hours and then poured into an excess of cold aqueous five percent sodium bicarbonate solution. The methylene chloride layer was separated, dried with anhydrous sodium sulfate and thereupon evaporated to give a dry residue of 2 methyl 9a fluoro-l1,9,17a,20fl,21-tetrahydroxy-4-pregnen-3-one 20,21-diacetate. The material was purified by recrystallization from acetone and Skellysolve B hexanes and the thus purified Z-IIICthYI-Qu-flllOIO- 11B,170:,205321-tetrahydroxy-4-pregnene-3-one 20,21 diacetate of melting point 232.5 to 236 degrees centigrade showed an infrared spectrum in chloroform equal to' the one postulated for the proposed compound.

EXAMPLE 28 2-ethyl-9a-fluor0-1 113,1 7 a,20;8,21 -tetrahydroxy-4-zpregnen- 3-0ne ZO-benzoate In the same manner as shown in Example 27 reacting; 2-ethyl-9p,l'lB-epoxyI7a,20fl,21-trihydroxy 4 pregnen- 3-one 20-benz-oate, ZI-acetate with hydrofluoric acid in 2? methylene chloride solution in the presence of a strong acid such as perchloric acid produced 2-ethyl-9a-fluoro l1 8,1704,2053l-tetrahydroxy-4-pregnen-3-one 20,8-henzoate, ZI-acetate.

EXAMPLE 29 In the same manner as shown in Example 27, treating with hydrofluoric acid in methylene chloride in the presence of perchloric acid.

(a) 2-methyl-9}3,1l/3-epoxy-l7a,20fi,21 trihydroXy-4- pregnen-S-one 20,2l-dipropionate produces Z-methyl-Qafiuoro 11 3,l7a,20[3,2l-tetrahydroxy-4-pregnen-3-one 20, 2l-dipropionate.

(b) 2-propyl-9;3,11,8-epoxy 17a,20fi,2l trihydroxy-4- pregnen-3-one 20-butyrate, 21-acetate produces Z-propyl- 9a-fluoro-l lfl,17a,20;8,21tetrahydroXy-4-pregnen 3 one ZO-butyrate, 21-acetate.

(c) 2-benzyl-95,11}3-epoxy 17a,20fi,21 trihydroxy-4- pregnen-3-one 20-valerate, 2l-acetate produces 2-benzyl- 9u-fluoro-1113,l7a,20fi,2l-tetrahydroxy-4-pregnen 3 one 20-valerate, ZI-acetate.

(d) 2-butyl-9fl,11,8-ep-oxy l7a,20fi,2l trihydroxy 4- pregnen-3-one 20,2l-dipropionate produces 2-butyl-9afluoro-l1 8,17a,20,8,21-tetrahydroXy-4-pregnen-3 one 20, ZI-dipropionate.

(e) 2-heXyl-9fl,l 1,8 epoxy 170520511 trihydroxy-4- pregnen-3-one 20,21-diphenylpropionate produces 2-hexyl- 9a-fluoro-11,8,l7oc,20fi,2l-tetrahydroxyl-pregnen 3 one 20,2l-diphenylpropionate.

(f) 2-octyl-9;8,l1;3 epoxy l7a,20;3,2l trihydroXy-4- pregnen-3-one 20,21-dihexanoate produces Z-OCtYl-Qctfiuoro-l1 3,17a,20;3,2l-tetrahydroXy-4-pregnen-3 one 20, 21-dihexanoate.

EXAMPLE 30 2-methyl-9a-i0d0-11B,] 7a,20;8,21- tetrahydrxy-4- pregnen-3-0ne 20,21-diacetate In the same manner as shown in Example 27 Z-methyl- 9 8,115 epoxy-l7a,20;3,2l-trihydroxy-4-pregnen-3-one 20, Zl-diacetate was dissolved in methylene chloride and reacted with a solution of hydriodic acid in the presence of one percent of perchloric acid calculated on the total volume of solution to give 2-methyl-9a-iodo-11,8,17a,20;8, 21-tetrahydroXy-4-pregnen-3-one 20,21-diacetate.

In the same manner as shown in Examples 27 through 30 decomposing 2-lower-alkyl-9fi,11fi-epoxy-17a,20}3,2ltrihydroXy-4-pregnen-3-one 20,21-diacylate wherein the 2-lower-alkyl group is selected from methyl, ethyl, propyl, butyl, heXyl, heptyl, octyl, phenyl and benzyl and the like and wherein the acyl group of the acylate is selected from organic carboxylic acids, preferably hydrocarbon carboxylic acids containing from one to eight carbon atoms, inclusive, with hydrogen halide in the presence of a strong mineral acid such as perchloric, sulfuric acid or a benzenesulfonic acid, illustratively toluenesulfonic acid, produces the corresponding 2-lower-alkyl-9a-halo- 11,6,l7a,20[3,21-tetrahydroxy 4 pregnen-3o-ne 20,21-diacylate wherein the halogen atom has an atomic weight from 17 to 130, inclusive.

EXAMPLE 31 2 methyl 9a flame-11.8,]7a,20;8,2Z-tetrahydroxy-4- pregnen-S-one One gram of 2-methyl-9ot-fluoro-ll,8,l7a,20fi,2l-tetrahydroxy-4-pregnen-3-one 20,21-diacetate was dissolved in fifteen milliliters of methanol. Through the solution was bubbled oxygen free nitrogen for a period of ten minutes. Thereafter was added ten milliliters of methanol containing one gram of potassium carbonate and two milliliters of water. The aqueous alcoholic potassium carbonate solution had previously been purged of air by the same method, that is bubbling oxygen free nitrogen through the solution for a period of ten minutes. The thus obtained mixture is heated in a nitrogen atmosphere to reflux for a period of forty minutes and thereafter cooled and poured into 200 milliliters of cracked ice. The thus 28 obtained solution was extracted with two SO-milliliter portions of methylene chloride. The methylene chloride extracts were dried, evaporated and the residue was recrystallized from Skellysolve B heXanes-acetone to give pure 2-methyl 9a fluoro-l 1p,17a,20p,2 l-tetrahydroXy-4- pregnen-3-one.

EXAMPLE 32 Z-methyl 9a flu0r011/3,1 7a,20,B,21-tetrahydr0xy-4-pragnene-3-0ne 21 -trimethylacetate A mixture containing one gram of 2-methyi-9a-fiuorollfi, l7a,20fi, 21-tetrahydroxy-4-pregnen-3-one, five milliliters of pyridine and one milliliter of trimethylacetyl chloride was heated to a temperature of fifty degrees for a period of four hours. Thereafter the reaction mixture was poured into thirty milliliters of ice Water and the thus obtained precipitate collected on filter and recrystallized from ethyl acetate and Skellysolve B hexanes, to give pure Z-methyl 9a fluoro-l1,8,17or,20/3,2l-tetrahydroxy-4- pregnen-3-one ZI-trimethylacetate.

In a manner similar to Example 31, 2-methyl-9e-fluorollb,l7ot,20fi,2l-tetrahydroxy 4 pregnen-3-one may be esterified selectively in the 2l-position with halides of sterically hindered acid such as, for example, the chlorides and bromides of trimethylacetic acid, triethylacetic acid, dineopentylacetic acids, or the like.

EXAMPLE 33 2 methyl 9a flu0r0-17a,20,8,21-rrihydroxyl-pregnen- 3,11-di0ne 20,21 -a'iacetate A mixture was prepared containing 0.5 gram of 2- methyl-9a-fluoro 11,3,17vz,20fi,21 tetrahydroxy-4-pregnen-3-one, 20,21-diacetate, 0.2 gram of chromic anhydride, ten milliliters of glacial acetic acid and one-half milliliter of water. This mixture was stirred and thereupon maintained eight hours at room temperature. Thereafter the mixture was poured into fifty milliliters of ice Water and neutralized by the addition of dilute sodium hydroxide. The precipitate thus obtained was collected on a filter and recrystallized from ethyl acetone and Skellysolve B hexanes, three times, to give pure 2-metl1yl-9a.-fiuoro- 17a,20fl,2l-trihydroXy-4-pregnene-3,l l-dione 20,2 l-diacetate (2-II1BlIi1YI-9drflll0l'0-l70t-hydl'OXy-2Gfl,2 1-diacetoxy-4- pregnene-3,1l-dione).

EXAMPLE 34 In the same manner given in Example 33, oxidizing in acetic acid solution with chromic anhydride in the presence of a small amount of Water:

(a) 2 ethyl-9a-fiuoro-l1,6,l7ot,20fii,2l-tetrahydroxylpregnen-3-one ZO-benzoate, Zl-acetate produces 2-ethyl 9a-fluoro-l7ot,20 8,2l-trihydroxy 4 pregnene-3,ll-dionc ZO-benzoate, 21-acetate.

(b) 2-methyl fiuoro-l1p,l7a,20/8,2l-tetrahydroxy- 4-pregnen-3-one 20,2l-dipropionate produces 2rnethyl-9afluoro-17a,20fl,2l-trihydroXy-4-pregnene-3,l l-dione 20,21- dipropionate.

(c) Z-propyl 9a fluoro-l1B,l7rx,20fi,2l-tetrahydroxy- 4-pregnen-3-one ZO-butyrate, 21 -acetate produces 2- propyl 9c. fiu0ro-l7a,20,5,2l-trihydroxy-4-pregnen-3,l ldione 20-butyrate, 21-acetate.

(d) 2-benzyl 90c fluoro-l1,8,17u,20e,2l-tctrahydroxy- 4-pregnen-3-one 20-valerate, 2l-acetate produces Z-benzyl- 9ct-fiuoro-l7ot,20fi,2l-trihydroxy 4 pregnene-3,ll-dionc 20-valerate, 2l-acetate.

(e) 2 butyl-9a-fluoro-l 1 3, 17a,20;8,2l-tetrahydroXy-4- pregnen-3-one 20,21-dipropionate produces 2-butyi-9afluoro-l7a,20fi,2l-trihydroxy-4-pregnene-3,l l-dione 20,21-

dipropionate.

(f) 2-heXyl-9u fiuoro llfl,l7a,2il,6,2l-tetrahydroxy- 4-pregnen-3-one 20,21-diphenylpropionate produces 2- hexyl-9rx-fluoro-l7u,20l3,2l-trihydroxy 4 pregnene-3,lldione 20,21-diphenylpropionate.

(g) 2-octyl 90c fluoro-l1p ,17a,20,6,21-tetrahydroxy- 4-pregnen-3-one 20,21-dihexanoate produces 2-octyl-9w '29 fluoro-17a,2013,21-trihydroxy=4 pregnene-3,1l-dione 20,21-

dihexanoate.

In the same manner as shown in Examples 32 and 33 oxidation of 2 1ower-alkyl 9a-fluoro-1 1p,17tt,2()fi,21-tetrahydroxyl pregnen-la one 20,21- diacylate wherein the lower-alkylhas from one to eight carbon atoms and the acyl oftheacylate' of the esters is of a hydrocarbon carboxylicacid containing from one'to eight carbon atoms,

inclusive, produces the other corresponding 2-loWer-alkyl- 9ix-'fluoro 17a,20[3,21-trihydroxy 4 pregnene-3,11-dione 20,2l-diacylates.

EXAMPLE 3'5 A mixture of 0.5 gram of 2-methyl-9a-fluoro-17a,20,8, 21-trihydroxy-4-pregnene-3,1l-dione, five milliliters ofv pyridine and one milliliter of trimethylacety-l chloride was allowed to stand at room temperature for a. period of eighteen hours. Thereafter the mixture was-poured into fifty milliliters of cold water and thereaction mixture extracted with two 25-milliliter portions of methylene chloride. Methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and evaporated and the thus produced residue was recrystallized from ethyl acetate-Skellysolve B-hexanes to give pure 2- methyl-9a-fluoro-17a,20fi,21 trihydroxy 4 pregnene- 3,1-l-dione 21-trimethylacetate.

In the same manner as shownin Example 35- other selectively esterified 2-lower-alkyl-9arfluoro-l7a,20,B,21-' tetrahydroxy-4-pregnene-3,1-l-dione 2l-acylates are pre-' pared by reacting the corresponding 2-lower'-alkyl-9oc-' fluoro-17 x,20[3,21-trihydroxy-4-pregnene-3,1l-dione with a halide of a sterically hindered acid such as the chlorides and bromides oftrimethylacetic acid, triethylacetic acid, dineopentylaceticacidorthelike.

EXAMPLE 3'7 2 methyl-9a-flu0r0liydfocortisorie ZI-friinetltylaceaie One gram of 2-rnethyl-9u-fluor'o-1113,17a,20fi21 tetrahydroxy 4- pregnen- 3' one 21' trimethylacetate (Ex ample 32) was stirred for aperiod of 96"hours' at room temperature (about 22 to 25 degrees centigrade) with one gramof manganese dioxide freshly'prepared' in the mannot shown by Attenburrow et all, Journ; Chem. Soc, 1094 (1952) in 75 milliliters of methylene dichloride. Themixture' was then filtered to remove the manganese dioxide. The precipitated ma with methylene dichloride and the washings and methylene dichloridefiltrate combined, dried and evaporated to give a residue which was recrystallized from acetone and Skellysolve' B he'xan'es to" give pure 2-methyl-9lx-fluoro- 11,8,17'oc,21 trihydroxy 4 pregnene 3,20 dione 21- trimethylacetat'e I (2 methyl 91x flu'orohydrocortisone trimethylacet'ate): p

In the same maner as shown in Example 37 the 2- methyl-9a-fluorohydrocortisone' 21-trimethylace-tate is hydrolyzed with potassium carbonate in ethanol solution in a nitrogen atmosphere to give the free alcohol 2-methyl- 90c fluoro 11B,17a,21 trihydroxy 4 pregnen'e 3,20- dione (2-methyl-9a fluorohydrocortisone) possessing several times the gl'ucoc'orti'c'oid activity of the parent compound, hydrocortisone.

Treating the solution of 2-me'thyl-9a-fiuorohydrocortisone in pyridine with an acyl halide or acid anhydride of ngalnese dioxide was washed droxy-4-pregnene 3,l l-dione ZI-trimethylacetate yielded an' organic carboxylic acid preferably of a hydrocarbon In the same manner as shown in Example 37 oxidizing.

with f-reshly precipitated manganese dioxide in methylene dichloride solution 2-methyl-9a-fluoro-1704,2052l-trihythe 2-methyl-9ix-fiuoro-1 7a,20,6,21-trihydroxy-4-pregnene- 3,11,20 trione- (2- methyl 9a-- fluoro cortisone) 21- trim'ethylacetate;

In the sameman'ner as shown in Examples 37- and'38 oxidizing 2 lower alkyl 9oz fluoro 11 ;3,l7a',2 0B,2-1- tetrahydroxy'- 4 pregnen 3 one or 2- lower alkyl 9a fluoro 17a,20fl,21 trihydroxy 4 pregnene 3,11- dione 2l-acylates wherein the lower-alkyl group has-from one toeight carbon atoms and the 21-a-cyloxy group is of ahydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, with manganese dioxide in anon-oxidizable solvent such as methylenechlo'ride, chloro-- form,-carbon tetrachloride, hexanes, heptanes orthe like, produces the corresponding 2'-lower'-alkyl-9a-fiuorohydrocortisone 2'l -ester respectively the 2lower-alkyl 9d-fiuoro cortisone 21'-cster'.

Through hydrolysis performed-in Example 14 and subsequent reest erifi'ca'tion other esters of 2-lower-a'1kyl-9otfluorohydrocortisone and 2-lower-alkyl-9a-fiuoro cortisone can be' produced. Vigorous esterification procedures" at high temperatures, above seventy degrees centigrade', give" the acy-latesof 2-m'e'thyl-9a-fluorohydrocortisone wherein the 11B; the and the 21-positi0n are esterified. Vigorous conditions used on 2-lower-alkyl9ot-fiuoro cortisone produces the diester that is 2-loWer-alkyl-9'a-fluorocortisone- 17a,21-diacylate, which are active adrenocortical hormones with p'r'olonged action.

I It; is t'o' be understood that the invention is not to belimited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 2 methyl 17ot,20fi',2l trihydroxy 4 pregnene- 3,11-dione.

2'. 2- methyl- 115,17a,20fi-,21 tetrahydroxy 4 pregnen'-=3-one.

3. 2 methyl 96,11 3 epoxy 17u,2OB,21 trihydroxy-4 -pre'gne'n-3-one 20;2'1-diacetate.

4. 2 -methyl 9a fluoro l-l/3,l7a,20{i,21 tetrahy droxy-4-pregnen-3-on'e.

5. 2 7 methyl 9a fluoro 1l,B,l7a,20B,2l' tetrahydroxy-4-pregnen-3'-one 20,2 l-di'acetate.

6. 2 -methyl 9a -fluoro 17a,20fi,21 trihydroxy 4- pregnene-3,l1-dione.

7. A process for the production of a 2-lower-alkyl-9afluoro 1-1,8,17u,2l),2'1 tetrahydroxy 4 pregnen 3- one which comprises the following steps: (1) treating a 1138 hydroxy- 21- acyloxy 4,17(20) [trans] pregnadi'en-3-one wherein the ac yloxy group is of" an organic carboxylic acid containing from one" to eight carbon atoms with a lower-alkyl ester of oxalic acid in the presence or" an alkali metal base to give the corresponding alkali-metal enolate of 2 lower alkyloxyox-alyl 11B hydroxy- 21 ac'yloxy 4,17(20) [trans] pregnadien 3 one wherein the alkyl group contains from one to eight carbon atoms and the alkali metal has an atomic weight between six and. forty; (2) treating the thus produced alkalimet-al enolater of 2-l'ower-alkyloxyoxalyl-1lfl=hydroxy 21- acyloxy 4,17 (20) [trans] pregnadien 3 -one with a lower-alkyl halide, wherein alkyl is defined as before, and the halogen is of atomic weight between 34 and 130, to give the corresponding 2-lower-alkyloxyoxalyl-Z-loweralkyl 115 hydroxy 21 acyloxy 4,l7(20) [translpregnadien-3-one; (3) hydrolyzing the 2-lower-alkoxyoxalyl 2 lower alkyl 115 hydroxy 21 acyloxy- 4,17(20) [trans] pregnadien 3 one with an alkali alkoxide wherein alkali is defined as before and wherein the alkyl group of the alkoxy group is defined as before to give the corresponding 2-lower-alkyl-115,21-dihydroxy- 4,17(20) [trans] pregnadien 3 one; (4) treating the thus produced 2 lower alkyl 115,21 dihydroxy 4,17(20) [trans] pregnadien 3 one with an esterifying agent selected fromhalides and anhydrides of organic carboxylic acids containing from one to eight carbon atoms, inclusive, to obtain the corresponding 2- lower alkyl 115 hydroXy 21 acyloxy 4,17(20)- [trans]-pregnadien-3-one; (5) treating the thus obtained 2 lower alkyl 115 hydroxy 21 acyolxy 4,17(20)- [trans]-pregnadien-3-one with osmium tetroxide in tertiary butyl alcohol in the presence of pyridine to obtain an intermediate 17(20)-osmate which is decomposed with aqueous sulfurous acid to give a 2 lower alkyl- 175,17a,205 trihydroxy 21 acyloxy 4 pregnen 3- one; (6) esterifying the thus produced 2-lower-alkyl- 115,17a,205 -trihydroxy 21 acyloxy 4 pregnen 3- one with an acylating agent selected from halides and ,anhydrides of organic carboxylic acids containing from one to eight carbon atoms, inclusive, to give a 2-1o-weralkyl 115,17a dihydroxy 205,21 diacyloxy 4 pregnen-3-one; (7) treating the thus produced 2-lower-alkyl- 115,170: dihydroxy 205,21 diacyloxy 4 pregnen 3 one with an N-halo compound selected from the group consisting of N-haloamide and N-haloimide, and treating the thus obtained product with anhydrous sulfur dioxide to produce the 2 -lower alkyl 17a hydroxy-205,21- diacyloxy 4,9(11) pregnadien 3 one; (8) treating the thus produced 2-lower-alkyl-17a-hydr0Xy-205,21-diacyloxy 4,9(11) pregnadien 3 one with a hypohalous acid in which the halogen atom has an atomic weight between 34 and 130 to give the corresponding 2- lower alkyl 9oz halo 115,175 dihydroxy 205,21

diacyloxy-4-pregnen-3-one; (9) treating the thus produced 2 lower alkyl 9a halo 115,17a dihydroxy 205,21- diacyloXy-4-pregnen-3-one with anhydrous alkali acetate, wherein alkali is defined as before, in a substantially water-free solvent to yield the corresponding epoxy compound, 2 lower alkyl 95,115 epoxy 17a hydroxy- 205,21 diacyloxy 4 pregnen 3 one; 10) treating the thus produced 2 lower alkyl 95,115 epoxy- 170: hydroxy 205,21 diacyloxy 4 pregnen 3 one with hydrogen fluoride in the presence of a strong acid to give the corresponding 2-lower-alkyl-9a-fiuoro-l15,170:- dihydroxy 205,21 diacyloxy 4 pregnen 3 one; and (11) hydrolyzing in an alkali medium the thus produced 2 lower alkyl 9a luoro 115,171: dihydroxy- 205,21 diacyloxy 4 pregnen 3 one to obtain the corresponding 2 lower alkyl 9a fiuoro 11,3,17oc, 205,21-tetrahydroxy-4-pregnen-3-one.

8. A process for the production of 2-methyl-9a-fluoro- 1l5,17a,205,21-tetrahydroXy-4-pregnen-3-one which com prises the following steps: (1) treating a 115-hydroxy-21 acetoxy-4,17()-[trans]-pregnadien-3-one with a loweralkyl ester of oxalic acid in the presence of an alkali metal alkoxide to give the corresponding 2-lower-alkyloxyoxalyl-115 hydroxy 21 acetoxy 4,17(20) -[trans]-pregnadien-3-one wherein the alkyl group contains from one to eight carbon atoms and the alkali metal has an atomic weight between six and forty; (2) treating the thus produced alkali-metal enolate of 2-loWer-alkyloXyoXalyl-115- hydroxy 21 acetoxy 4,17(20) [trans] pregnadien- 3-one with a methyl halide wherein the halogen is of atomic weight between 34 and 130, to give the corresponding 2-lower-alkyloXyoxalyl-2-methyl-115-hydroxy-21-acetoxy-4, 1 7 20) [trans] -pregnadien3-one; (3) hydrolyzing the 2-10wer-alkyloxyoxalyl-Z-methyl-115-hydroxy-21-acetoXy-4,17(20)-[transl-pregnadien-3-one with an alkali alkoxide wherein alkali is defined as before and wherein the alkyl group of the alkoxy group is defined as before to give 2-methyl-115,21-dihydroxy-4,17(20)-[trans]-pregnadien-3-one; (4) treating the thus produced Z-methyl- 115,21 dihydroxy 4,17(20) [trans] pregnadien 3- one with acetic anhydride to obtain the 2-methyl-1l5- hydroxy 21 acetoxy 4,17(20) [trans] pregnadien- 3-one; (5) treating the thus obtained 2-methyl-115-hydroxy 21 acetoxy 4,17(20) [trans] pregnadien 3- one with osmium tetroxide in tertiary butyl alcohol in the presence of pyridine to obtain an intermediate 17(20)- osmate which is decomposed with aqueous sulfurous acid to give Z-methyl-l15,17a,205-trihydroxy-21-acetoxy-4- pregnen-El-one; (6) treating the thus produced 2-methyl- 115,17a,205 trihydroxy 21 acetoxy 4 pregnen 3- one with acetic anhydride to obtain 2-methyl-115,17adihydroxy-205,21-diacetoXy-4-pregnen-3-one; (7) treating the thus produced 2-methyl-115,17q-dihydroXy-205,21-diacetoXy-4-pregnen-3-one with N-halo compound selected from the group consisting of N-haloamides and N-haloirnides and treating the thus obtained product with anhydrous sulfur dioxide to produce the 2-methyl-17a-hydroxy 205,21 diacetoxy-4,9(11)-pregnadien-3-one; (8) treating the thus produced 2-methyl-17rz-hydroXy-205,21 diacyloXy-4,9(1l)-pregnadien-3-one with a hypohalous acid in which the halogen atom has an atomic weight between 34 and to give the corresponding 2-methyl-9ahalo 115,17 dihydroxy 205,21 diacetoxy 4 pregnen-3-one; (9) treating the thus produced 2-methyl-9ahalo 115,170 dihydroXy-205,21-diacetoxy-4-pregnen-3- one with anhydrous alkali acetate wherein alkali is defined as hereinbefore in a substantially water-free solvent to yield 2 methyl-95,115-epoXy-17a-hydroXy-205,21-diacetoxy-4-pregnen-3-one; (10) treating the thus produced 2- methyl 95,115 epoxy-17a-hydroxy-205,21-diacetoxy4- pregnen-3-one with hydrogen fluoride in the presence of a strong acid to give 2-methyl-9u-fiuoro-115,17a-dihydroXy- 205,21-diacetoxy-4-pregnen-3-one, and (11) hydrolyzing in an alkali medium the thus produced 2-methyl-9a-fiuorol l5,17a-dihydroXy-205,21-diacyloxy-4-pregnen-3-one to obtain the corresponding 2-methyl-9a-fluoro-115,17a,205,- 21-tetrahydroxy-4-pregnen-3-one.

9. A compound selected from the group consisting of 2 lower alkyl 115,17a,205 trihydroxy 21 acyloxy- 4-pregnen-3-one, 2-lower-alkyl-115,17a-dihydroxy-205,21- diacycloxy-4-pregnen-3-one, and 2-lower-alkyl-115,17a,- 205,21-tetrahydroxy-4-pregnen-3-one, wherein the lower alkyl radical contains from one to eight carbon atoms, inclusive, and wherein the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

10. A compound selected from the group consisting of 2 lower alkyl-17a-hydroxy-205,21-diacyloxy-4-pregnene-3,11-dione and 2-lower-alkyl-17u,205,21-trihydroxy- 4-pregnene-3,11-dione, wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive, and wherein the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

11. A compound selected from the group consisting of 2 lower alkyl 17oz hydroxy 205,21 diacyloxy- 4,9(11)-pregnadien-3-one and 2-lower-alkyl-17a,205,21- trihydroxy4,9(11)-pregnadien-3-one, wherein the loweralkyl radical contains from one to eight carbon atoms, inclusive, and wherein the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

12. A compound selected from the group consisting of 2 lower alkyl 9a halo 115,170; dihydroxy 205,21- diacycloxy-4-pregnen-3-one, 2-loWer-alkyl-9a-halo-115,- 17a,205 trihydroxy 21 trimethylacetoxy 4 pregnen-3-one, and 2-l0wer-alkyl-9a-halo-115,17a,205,21-tetrahydroxy-4-pregnen-3-one, wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive, where- 33 in the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and wherein the halo atoms are of atomic weight seventeen through 130.

13. 2 lower alkyl 95,115 epoxy 17oz hydroxy- 205,2l-diacyloxy-4-pregnen-3-one, wherein the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and wherein the lower-alkyl radical contains from, one to eight carbon atoms, inclusive.

14. A compound selected from the group consisting of 2 lower alkyl 90c halo 17oz hydroxy- 2013,21 diacyloxy 4 pregnene-3,11-dione, 2-lower-alkyl-9a-halo- 171,205 dihydroxy 21 trimethylacetoxy 4 pregnene- 3,11-dione, and 2-lower-alkyl-9u-halo-17a,20fl,21-trihydroxy-4-pregnene-3,1l-dione, wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive,

34 wherein the acyl group of acyloxy is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and wherein the halo atoms are of atomic weight seventeen through 130.

References Cited in "the file of this patent UNITED STATES PATENTS 2,281,622 Ruzicka May 5, 1942 2,286,892 Bockmuhl June 16, 1942 2,291,643 Marker Aug. 4, 1942 2,374,680 Hoehn .42... May 1, 1945 OTHER REFERENCES Hogg et aL: J. A. C. 8., December 5, 1955, pages 6401- 6402.

Fried et a1.: J. A. C. 8., March 5, 1954, pages 1455- 1456.

UNITEDUSTATES PATENT OFFICE Certificate of Correction Patent No. 2,852,538 September 16,1958

Mary i ficheri et al. W It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Columns 3 and 4, Formula X should appear as shown below instead of as in the patent:

CHzOR HOR Ito-A -on OHg column 4, line 56, for pregneas read pregnenes; line 60, for alkyloxyalyl read alkyloxyoxalyl; column 6, line 68, for tiphenylmethyl read -triphenylmethyl;

column 9, line 55, for thiry read thirty-; column 12, line 35, for are produce read are produced; column 14:, line 45, for idodie read -iodide; column 16, lines 28 and 29, for -11,,B21- read -11,8,21- column 22, line 71, for 21-triethylacetate read -21-trimethylacetate; column 30, line 61, for -11,8,17a,20,21- read 11,3,17oc,20,B,21--; column 31, line 19, for acyolxy read acyloxy; line 24,, for 17B,17a,20B- read -11,B,17cc,20,B---; column 32 lines 47 and 71, for diacycloxy, each occurrence, read diacylo*.:y.

Signed and sealed this 14th day of J uly 1959.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Oyficer. Uom/rm'ssz'oner of Patents. 

7. A PROCESS FOR THE PRODUCTION OF A 2-LOWER-ALKYL-9AFLUORO - 11B,17A,20,21 - TETRAHYDROXY - 4 - PREGNEN - 3 ONE WHICH COMPRISES THE FOLLOWING STEPS: (1) TREATING A 11B-HYDROXY-21-ACYLOXY-4,17(20)-(TARANS)-PREGNADIEN-3-ONE WHEREIN THE ACYLOXY GROUP IS OF AN ORGANIC CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS WITH A LOWER-ALKYL ESTER OF OXALIC ACID IN THE PRESENCE OF AN ALKALI METAL BASE TO GIVE THE CORRESPONDING ALKALI-METAL ENOLATE OF 2-LOWER-ALKYLOXYOXALYL - 11B-HYDROXY21 - ACYLOXY - ,127(20) - (TRANS) - PREGNADIEN - 3 - ONE WHEREIN THE ALKYL GROUP CONTAINS FROM ONE TO EIGHT CARBON ATOMS AND THE ALKALI METAL HAS AN ATOMIC WEIGHT BETWEEN SIX AND FORTY; (2) TREATING THE THUS PRODUCEDS ALKALIMETAL ENOLATE OF 2-LOWER-ALKYLOXYOXALYL-11B-HYDROXY-21ACYLOXY - 4,17(20) - (TRANS) - PREGNADIEN - 3 -ONE WITH A LOWER-ALKYL HALIDE, WHEREIN ALKYL IS DEFINED AS BEFORE, AND THE HALOGEN IS OF ATOMIC WEIGHT BETWEEN 34 AND 130, TO GIVE THE CORRESPONDING 2-LOWER-ALKYLOXYOXALYL-2-LOWER ALKYL - 11B - HYDROXY - 21 - ACYLOXY - 4,17(20) - (TRANS)PREGNADIEN-3-ONE; (3) HYDROLYZING THE 2-LOWER-ALKOXYOXALYL - 2 - LOWER - ALKYL - 11B - HYDROXY - 21 - ACYLOXY4,17(20) - (TRANS) - PREGNADIEN - 3 - ONE WITH AN ALKALI ALKOXIDE WHEREIN ALKALI IS DEFINED AS BEFORE AND WHEREIN THE ALKYL GROUP OF THE ALKOXY GROUP IS DEFINED AS BEFORE TO GIVE THE CORRESPONDING 2-LOWER-ALKYL-11B,21-DIHYDROXY4,17(20) - (TRANS) - PREGNADIENE - 3 - ONE; (4) TREATING THE THUS PRODUCED 2 - LOWER - ALKYL - 11B,21 - DIHIYDROXY - 4,17(20) - (TRANS) - PREGNADIEN - 3 - ONE WITH AN ESTERIFYING AGENT SELECTED FROM HALIDES AND AND ANHYDRIDES OF ORGANIC CARBOXYLIC ACIDS CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, TO OBTAIN THE CORRESPONDING 2LOWER - ALKYL - 11B - HYDROXY - 21 - ACYLOXY - 4,17(20)(TRANS)-PREGNADIEN-3-ONE; (5) TREATING THE THUS OBTAINED 2 - LOWER - ALKYL - 11B - HYDROXY - 21 - ACYOLXY -4,17(20)-U (TRANS)-PREGNADIEN-3-ONE WITH OSMIUM TETROXIDE IN TERTIARY BUTYL ALCOHOL IN THE PRESENCE OF PYRIDINE TO OBTAIN AN INTERMEDIATE 17(20)-OSMATE WHICH IS DECOMPOSED WITH AQUEOUS SULFUROUS ACID TO GIVE A 2 - LOWER - ALKYL17B,17A,20B - TRIHYDROXY - 21 - ACYLOXY - 4 - PREGNEN - 3 ONE; (6) ESTERIFYING THE THUS PRODUCED 2-LOWER-ALKYL11B,17A,20B -TRIHYDROXY - 21 - ACYLOXY - 4 1 PREGNEN - 3 ONE WITH AN ACYLATING AGENT SELECTED FROM HALIDES AND ANHYDRODES OF ORGANIC CARBOXYLIC ACIDS CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, TO GIVE A 2-LOWERALKYL - 11B,17A-DIHYDROXY - 20B,.21 - DIACYLOXY - 4 - PREGNEN-3-ONE; (7) TREATING THE THUS PRODUCED 2-LOWER-ALKYL11B,17A - DIHYDROXY - 20B,21 - DICYLOXY - 4 - PREGNEN - 3 ONE WITH AN N-HALO COMPOUND SELECTED FROM THE GROUP CONSISTING OF N-HALOAMIDE AND N-HALOIMIDE, AND TREATING THE THUS OBTAINED PRODUCT WITH ANGTDROUS SULFUR DIOXIDE TO PRODUCE THE 2-LOWER - ALKYL - 1(A - HYDROXY-20B,21DIACYLOXY - 4,9(11) - PREGNADIEN - 3 - ONE; (8) TREATING THE THUS PRODUCED 2-LOWER-ALKYL-17A-HYDROXY-20B,21-DIACYLOXY - 4,9(11) - PREGNADIEN - 3 - ONE WITH A HYPOHALOUS ACID IN WHICH THE HALOGEN ATOM HAS AN ATOMIC WEIGHT BETWEEN 34 AND 130 TO GIVE THE CORRESPONDING 2LOWER - ALKYL - 9A - HALO - 11B,17A - DIHYDROXY - 20B,21DIACYLOXY-4-PREGNEN-3-ONE; (9) TREATING THE THUS PRODUCED 2 - LOWER - ALKYL - 9A - HALO - 11B,17A-DIHYDROXY - 20B,21DIACYLOXY-4-PREGNEN-3-ONE WITH ANHYDROUS ALKALI ACETATE, WHEREIN ALKALI IS DEFINED AS BEFORE, IN A SUBSTANTIALLY WATER-FREE SOLVENT TO YIELD THE CORRESPONDING EPOXY COMPOUND, 2 - LOWER - ALKYL - 9B,11B-EPOXY-17A - HYDROXY20B,21 - DIACYLOXY - 4 - PRENEN - 3 - ONE; (10) TREATING THE THUS PRODUCED 2 - LOWER - ALKYL - 9B,11B -EPOXY17A - HYDROXY-20B,21 - DIACYLOXY - 4 - PREGNEN - 3 - ONE WITH HYDROGEN FLUORIDE IN THE PRESENCE OF A STRONG ACID TO GIVE THE CORRESPONDING 2-LOWER-ALKYL-9A-FLUORO-11B,17ADIGYDROXY - 20B,21 - DIACYLOXY - 4 - PREGNEN - 3 - ONE; AND (11) HYDROLYZING IN AN ALKALI MEDIUM THE THUS PRODUCED 2 - LOWER - ALKYL - 9A-FLUORO-11B,17A-DIHYDROXY20B,21 DIACYLOXY - 4 - PREGNEN - 3 -1 ONE TO OBTAIN THE CORRESPONDING 2 - LOWER - ALKYL - 9A - FLUORO - 11B,17A, 20B,21-TETRAHYDROXY-4-PREGNEN-O-ONE
 12. A COMPOUND SELECTED FROM THE FROUP CONSISTING OF 2 - LOWER - ALKYL - 9A - HALO - 11B,17A - DIHYDROXY - 20B,21DIACYCLOXY-4-PREGNEN-3-ONE, 2-LOWER-ALKYL-9A-HALO-11B17A,20B - TRIHYDROXY - 21 - TRIMETHYLACETOXY - 4 - PREGNEN-3-ONE, AND 2-LOWER-ALKYL-9A-HALO-11B,17A,20B,21-TETRAHYDROXY-4-PREGNEN-3-ONE, WHEREIN THE LOWER-ALKYL RADICAL CONTAINS FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, WHEREIN THE ACYL GROUP OF ACYLOXY IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, AND WHEREIN THE HALO ATOMS ARE OF ATOMIC WEIGHT SEVENTEEN THROUGH
 130. 